1,2,4-oxidiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents

ABSTRACT

Compounds of the formula ##STR1## wherein: R 1  is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxy, or cyanomethyl; 
     Y is alkylene of 3 to 9 carbon atoms, 
     R 2  and R 3  independently are hydrogen, alkyl, alkoxy, halo, cyano, trifluoromethyl and nitro; 
     R 4  is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl, dihaloethyl, cycloalkyl, heterocyclyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, halo, thioalkyl, alkylthioalkyl, alkylthio, thio, 2,2,2-trifluoro-ethyl, (4-methylphenyl)sulfonyloxymethyl, N=Q or CON=Q, where N=Q is amino, alkylamino or dialkylamino; 
     R 5  is hydrogen or halo or alkyl.

REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/131,050, filedon Oct. 1, 1993, U.S. Pat. No. 5,464,848 which in turn is a continuationin part of application Ser. No. 07/869,287, filed Apr. 15, 1992, U.S.Pat. No. 5,349,068.

BACKGROUND OF THE INVENTION

a) Field of the Invention

This invention relates to novel1,2,4-oxadiazolyl-phenoxyalkylisoxazoles, to methods for the preparationthereof, and compositions and methods for the use thereof as antiviralagents.

b) Information Disclosure Statement

Diana U.S. Pat. No. 4,843,087, issued Jun. 27, 1989, disclosesheteryl-phenoxyalkylisoxazoles, wherein the heteryl moiety is an oxazoleor an oxazine, which exhibit antiviral activity.

Diana et al. U.S. Pat. No. 4,857,539, issued Aug. 15, 1989, disclosesantivirally active compounds of the formula ##STR2## wherein:

Y is an alkylene bridge of 3-9 carbon atoms;

Z is N or HC:

R is hydrogen or lower-alkyl of 1-5 carbon atoms, with the proviso thatwhen Z is N, R is lower-alkyl;

R₁ and R₂ are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro,lower-alkoxycarbonyl or trifluoromethyl; and

Het is selected from specified heterocyclic groups. Included in thedefinition of Het is unsubstituted 1,3,4-oxadiazol-2-yl andunsubstituted 1,2,4-oxadiazol-5-yl.

Diana et al. U.S. Pat. No. 4,861,791, issued Aug. 29, 1989, disclosesantivirally active compounds of the formula, inter alia, ##STR3##wherein:

Y is an alkylene bridge of 3 to 9 carbon atoms optionally interrupted byone or two oxygen atoms, by cyclohexyl or by an olefinic linkage;

X is O, S, SO or SO₂ ;

Z is N or R₈ C, where R₈ is hydrogen or lower-alkanoyl;

R₁ and R₂ are selected from the group consisting of hydrogen,lower-alkyl, lower-alkenyl, halogen, nitro, lower-alkoxy,lower-alkylthio, difluoromethyl, trifluoromethyl, amino,lower-alkanoylamino, di-lower-alkylamino, hydroxy, lower-alkenoyl,lower-alkanoyl, hydroxymethyl and carboxy;

R and R₃ are each hydrogen or alkyl of 1 to 3 carbon atoms optionallysubstituted by a member of the group consisting of hydroxy,lower-alkanoyloxy, lower-alkoxy, halo or N=Z', wherein N=Z' is amino,lower-alkanoylamino, lower-alkylamino, di-lower-alkylamino,1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl; with the proviso that whenZ is N, R is other than hydrogen; and

Het is selected from specified heterocyclic groups includingunsubstituted 1,3,4-oxadiazol-2-yl.

Diana et al. U.S. Pat. No. 4,942,241, issued Jul. 17, 1990, disclosesantivirally active compounds of the formulas ##STR4## wherein:

Y is an alkylene bridge of 1-9 carbon atoms;

R' is lower-alkyl or hydroxy-lower-alkyl of 1-5 carbon atoms;

R₁ and R₂ are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro,lower-alkoxycarbonyl or trifluoromethyl; and

R₈ is hydrogen or lower-alkyl of 1-5 carbon atoms.

Diana U.S. Pat. No. 4,945,164, issued Jul. 31, 1990, disclosesantivirally active compounds of the formula, inter alia, ##STR5##wherein:

Y is an alkylene bridge of 3-9 carbon atoms;

R' is lower-alkyl or hydroxy-lower-alkyl of 1-5 carbon atoms;

R₁ and R₂ are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro,lower-alkoxycarbonyl or trifluoromethyl; and

R₈ is hydrogen or lower-alkyl of 1-5 carbon atoms.

Commonly assigned G. D. Diana and T. R. Bailey U.S. patent applicationSer. No. 07/731,569, filed Jul. 17, 1991, discloses compounds of theformula ##STR6## wherein:

Y is alkylene of 3 to 9 carbon atoms;

R₁ is lower-alkyl, lower-alkoxy-(C₁₋₃ -alkyl), lower-alkoxycarbonyl,cyclopropyl or trifluoromethyl;

R₂ and R₃ independently are hydrogen, lower-alkyl, halogen,lower-alkoxy, nitro, trifluoromethyl or hydroxy; and

R₄ is hydrogen or lower-alkyl; where lower-alkyl and lower-alkoxy, eachoccurrence, have from 1-5 carbon atoms;

with the proviso that when R₁ is lower-alkyl, at least one of R₂ and R₃is hydroxy.

SUMMARY OF THE INVENTION

In one aspect the invention provides a compound of the formula ##STR7##wherein:

R₁ is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl,hydroxyalkoxy, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxy,cyanomethyl;

Y is alkylene of 3 to 9 carbon atoms,

R₂ and R₃ independently are hydrogen, alkyl, alkoxy, halo, cyano,trifluoromethyl or nitro;

R₄ is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl,dihaloethyl, cycloalkyl, heterocyclyl, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, halo, thioalkyl,alkylthioalkyl, alkylthio, thio, 2,2,2-trifluoroethyl,2,2,2-trihaloethyl, (4-methylphenyl)-sulfonyloxy-methyl, N=Q or CON=Q,where N=Q is amino, alkylamino or dialkylamino;

R₅ is halo, or hydrogen, or alkyl.

In another aspect the invention provides a compound of the formula##STR8## wherein Y, R₂ and R₃ are as defined above and R₆ is alkoxy,fluoromethyl, difluoromethyl, trihalomethyl, cycloalkyl or alkoxyalkyl.

In another aspect the invention provides a compound of the formula##STR9## wherein R₂ and R₃ are as defined above and R₇ is alkoxy,fluoromethyl, difluoromethyl, trifluoromethyl, cycloalkyl, alkoxyalkylor cyano.

In other aspects the invention provides compounds of formulas XVII andXXI hereinafter.

In other aspects the invention provides a composition for combattingpicornaviruses which comprises an antivirally effective amount of acompound of formula I in admixture with a suitable carrier or diluentand to methods for combatting picornaviruses therewith includingcombatting a picornaviral infection in a mammalian host.

The compounds of formula I are useful as antipicornaviral agents.

The compounds of formulas III, IV, XVII and XXI are useful asintermediates for the preparation of the compounds of formula I.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

Preferred compounds of formula I are those wherein

R₁ is C₁₋₅ -alkyl, C₁₋₅ -alkoxy, hydroxy, cyclopropyl, hydroxy-C₁₋₅-alkyl, C₁₋₃ -alkoxy-C₁₋₅ -alkyl, hydroxy-C₁₋₅ -alkoxy,methylthiomethyl, methylsulfinylmethyl, methylsulfonylmethyl orcyanomethyl;

Y is alkylene of 3 to 9 carbon atoms, especially 3 to 5 carbon atoms;

R₂ and R₃ independently are hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkoxy or halo,cyano; and

R₄ is C₁₋₃ -alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl,cyclopropyl, C₁₋₃ -alkoxycarbonyl, hydroxy-C₁₋₃ -alkyl, C₁₋₃-alkoxy-C₁₋₃ -alkyl, (C₁₋₃ -alkane)carbonyloxy-C₁₋₃ -alkyl, cyano,2,2,2-trifluoroethyl, 4-(methylphenyl)sulfonyl-oxymethyl, N=Q or CON=Q,where N=Q is amino, C₁₋₃ -alkylamino, R₅ is hydrogen or di-(C₁₋₃-alkyl)amino.

R₅ is hydrogen, halo or alkyl.

More preferred compounds of formula I are compounds of the formula##STR10## wherein R₁, Y, R₂, R₃, and R₄ are as defined above for formulaI and R₅ is hydrogen and especially wherein R₁, Y, R₂, R₃ and R₄ are asdefined in the previous paragraph for the preferred compounds of formulaI.

Especially preferred are the compounds of formula I or IA wherein R₄ isC₁₋₃ -alkoxy, fluoromethyl, dihalomethyl, trihalomethyl, cycloalkyl orC₁₋₃ -alkoxy-C₁₋₃ -alkyl, especially trifluoromethyl.

It should be understood that in the compounds of the invention, when the1,2,4-oxadiazole ring is substituted by hydroxy, amino or alkylamino,they may exist in any of three possible tautomeric forms as follows:##STR11## wherein R₄ is hydroxy, amino or alkylamino and T is O, NH orN-alkyl, and such tautomers are within the purview of the invention.

As used herein, unless otherwise specifically defined, alkyl, alkane,alkoxy, cycloalkyl and halo each has the following meaning:

alkyl and alkoxy mean aliphatic radicals, including branched radicals,of from one to five carbon atoms. Thus the alkyl moiety of such radicalsinclude, for example methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, t-butyl and pentyl;

alkane means a monovalent aliphatic alkyl radical, including branchedradicals of from one to four carbon atoms. Thus the alkane moiety ofsuch radical includes, for example, methyl, ethyl, propyl, isopropyl,n-butyl and sec-butyl;

cycloalkyl means an alicyclic radical having from three to six carbonatoms as illustrated by cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; and

heterocyclyl refers to a 5 or 6 membered carbon based heterocycle,having from one to about three nitrogen atoms and/or one oxygen orsulfur atom, provided that no two oxygen and/or sulfur atoms areadjacent in the heterocycle. Examples include furyl, thienyl, pyridyl,oxadiazolyl, thiadiazolyl, triazinyl, pyrimidinyl and the like; and

halo means bromo, chloro, iodo or fluoro.

As used herein, in hydroxyalkyl and alkoxyalkyl, the hydroxy and alkoxygroups can occur at any available position of alkyl. Thus hydroxyalkyland alkoxyalkyl include, for example, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2, 3, 4 and5-hydroxy-pentyl and the like and corresponding alkyl ethers thereof.

As used herein, in hydroxyalkoxy, the hydroxy group can occur at anyavailable position of alkoxy other than the C-1 position. Thushydroxyalkoxy includes, for example, 2-hydroxyethoxy, 2-hydroxypropoxy,2-hydroxyisopropoxy, 2 and 5-hydroxypentoxy and the like.

The compounds of formula I wherein R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂, R₃ and R₅ are as defined hereinbefore, and R₄ ishydroxy, halomethyl, dihalomethyl, trihalomethyl, cycloalkyl,alkoxycarbonyl, alkoxyalkyl, alkane-carbonyloxyalkyl or2,2,2-trifluoroethyl, can be prepared by a process which comprisesreacting an amidoxime (N-hydroxy-carboximidamide) of the formula##STR12## with an acid halide, R₄ COX, an alkyl haloformate, ROCOX (inthe case where R₄ in formula I is hydroxy), where R is methyl or ethyl,or an acid anhydride, (R₄ CO)₂ O, where R₁, Y, R₂, R₃, R₄ and R₅ are asdefined above in this paragraph and X is bromo, chloro, fluoro or iodounder anhydrous conditions to form the corresponding compound of formulaI. The process involves the following methods. In one method, theamidoxime V is reacted with the acid halide or the acid anhydride in thepresence of an organic or inorganic base, e.g., pyridine, triethylamineor potassium carbonate, in an inert solvent, e.g., acetone, methylenechloride, chloroform, toluene or tetrahydrofuran, or in a base whichalso functions as the solvent, e.g., pyridine, at an elevatedtemperature (about 40°-130° C.) or at a reduced temperature (about0°-15° C.). In the latter case an intermediate O-acyl derivative[C(NH₂)=NOC(=O)--(R₄ or OR)] is isolated and heated at a temperature inthe range of about 100°-130° C. for a time sufficient for cyclization tothe oxadiazole of formula I to occur, generally about 5 minutes to 4hours. In another method, the amidoxime V is reacted with the acidhalide or acid anhydride in an acid which corresponds to the acid halideor acid anhydride at an elevated temperature (about 70°-100° C.).

The compounds of formula I where R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂, R₃ and R₅ are as defined hereinbefore, and R₄ isdihalomethyl, trihalomethyl, cycloalkyl, alkoxyalkyl,alkanecarbonyloxyalkyl or 2,2,2-trifluoroethyl can be prepared by aprocess which comprises reacting amidoxime V with the product obtainedby reaction of a carboxylic acid, R₄ CO₂ H, where R₁, Y, R₂, R₃ and R₄are as defined above in this paragraph, with the coupling agentN,N'-carbonyldiimidazole, prepared as described in the examples, in aninert solvent, e.g., tetrahydrofuran, chloroform, methylene chloride ortoluene, at an elevated temperature (about 40°-80° C.) to form thecorresponding compound of formula I.

The compounds of formula I wherein R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, and R₄ is aminocan be prepared by a process which comprises reacting amidoxime V, whereR₁, Y, R₂, R₃ and R₅ are as defined above in this paragraph, withcyanogen halide, CNX₁, where X₁ is bromo, chloro or iodo, in thepresence of a base, e.g., potassium or sodium bicarbonate, in analcoholic solvent, e.g., ethyl alcohol, at about room temperature togive the compound of formula I where R₄ is amino.

The compounds of formula I where R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore and R₄ is CH₂ CF₃and R₅ is hydrogen or alkyl can be prepared by reacting amidoxime Vwhere R₁ is as defined above in this paragraph and Y, R₂, R₃ are asdefined hereinbefore, with a ketene 1,3-propanedithiol acetal of theformula ##STR13## to give the corresponding compound of formula I.

The amidoxime V and ketene 1,3-propanedithiol acetal are reacted in thepresence of silver trifluoroacetate in an inert solvent, e.g.,tetrahydrofuran, dioxane, dimethylformamide or N-methylpyrrolidinone, ata temperature in the range of from about 60° to about 100° C. Preferablythe reaction is carried out in the dark.

The intermediate amidoxime V is prepared according to the following flowsheet: ##STR14##

The bromophenol VI reacts with the cuprous cyanide in an inert solventat an elevated temperature, e.g., in dimethylformamide at refluxtemperature to give the cyanophenol VII. The latter is reacted withhaloisoxazole VIII, where X₂ is chloro, bromo or iodo, in a dry inertsolvent, e.g., acetonitrile or N-methylpyrrolidinone, in the presence ofa base, e.g., potassium carbonate or sodium hydroxide, optionally in thepresence of a catalytic amount of potassium or sodium iodide, at anelevated temperature (50°-120° C.) to give cyano compound IX. The cyanocompound IX reacts with the hydroxylamine hydrochloride in the presenceof a base, e.g., potassium or sodium carbonate, sodium acetate or sodiumhydroxide, in an alcoholic solvent, e.g., ethyl alcohol, at an elevatedtemperature (50°-150° C.) to give the amidoxime V.

Certain intermediate compounds of formula IX wherein R₁ is alkyl,cycloalkyl or alkoxyalkyl and Y, R₂ and R₃ are as defined hereinbeforecan be prepared by reacting the ethinyl compound XII describedhereinafter with a nitrile oxide, R₁ C≡N→O, where R₁ is as defined abovein this paragraph, using a procedure similar to that describedhereinafter for the preparation of compound I from the ethinyl compoundIII.

The intermediate bromophenols of formula VI and cyanophenols of formulaVII belong to generically known classes of compounds and are readilyprepared by known procedures.

The intermediate haloisoxazoles of formula VIII can be prepared by theprocedure described in U.S. Pat. No. 4,843,087, i.e., by reacting analkali metal derivative of an isoxazole of the formula ##STR15## whereinR₁ is alkyl, alkoxy, trifluoromethyl, cycloalkyl or alkoxyalkyl, with adihalide, X₂ -Y'-X₂, where Y' is alkylene of 2 to 8 carbon atoms and X₂is as defined above The alkali metal derivative is prepared in situ bytreating isoxazole X with an organo-alkali metal base such asbutyllithium or lithium diisopropylamide under anhydrous conditions.

The compounds of formula I wherein R₁ is alkyl, cycloalkyl oralkoxyalkyl, Y, R₂, R₃ and R₅ are as defined hereinbefore, and R₄ isalkoxy, trihalomethyl, cycloalkyl, alkoxycarbonyl, alkoxyalkyl or2,2,2-trifluoroethyl, can be prepared by a process which comprisesreacting an ethinyl compound of formula III hereinabove, wherein R₆ hasthe meaning defined above in this paragraph for R₄, with a nitrile oxideof the formula R₁ C≡N→O which is prepared in situ from a hydroxyiminohalide of the formula R₁ C(X₃)=NOH, where X₃ is chlorine or bromine, inthe presence of an amine base, e.g., triethylamine, pyridine orN-methylpyrrolidine. The hydroxyimino halides, which may also beprepared in situ, belong to a generically known class of compounds andare readily prepared by conventional procedures, e.g., by reacting thecorresponding aldehyde oxime (R₁ C=NOH) with a halogenating agent, e.g.,N-chlorosuccinimide or bromine. The process for preparing the compoundsof formula I by reacting the ethinyl compound of formula III takes placeby heating the reactants in an inert polar solvent, e.g.,dimethylformamide or N-methyl-pyrrolidone, at a temperature in the rangeof about 20° to about 120° C.

The intermediate ethinyl compounds of formula III are prepared accordingto the following flow sheet: ##STR16##

The cyanophenol VII is reacted with haloalkyne XI, where X₂ is asdefined hereinbefore, using a procedure similar to that described abovefor the preparation of the cyano compound IX from compounds VII andVIII, to give the ethinyl compound of formula XII. Ethinyl compound XIIis reacted with the hydroxylamine hydrochloride, using a proceduresimilar to that described above for the preparation of amidoxime V fromcyano compound IX, to give the amidoxime of formula XIII. The amidoximeXIII is reacted with the acid halide R₄ COX, acid anhydride (R₄ CO)₂ O,carboxylic acid R₄ CO₂ H or ##STR17## using procedures similar to thosedescribed hereinbefore for the preparation of compounds of formula Ifrom amidoxime V.

The haloalkynes of formula XI belong to a generically known class ofcompounds.

The ethynyl compound XII can be acetylated using for example aceticanhydride, trifluoroacetylchloride, etc, giving the methyl or halomethylketone. This ketone is then reacted with a 2 moles of hydroxylamine togive the corresponding compound of formula V.

The compounds of formula I where R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, and R₄ is alkoxy,trihalomethyl, cycloalkyl, alkoxycarbonyl, alkoxyalkyl or2,2,2-trifluoroethyl, can be prepared by a process which comprisesreacting a phenol of the formula IV above wherein R₂ and R₃ are asdefined hereinbefore and R₇ is as defined above in this paragraph forR₄, with a haloisoxazole of formula VIII above where R₁ is as definedabove in this paragraph and Y and X₂ are as defined hereinbefore, togive the corresponding compound of formula I. The procedure used issimilar to that described above for the preparation of cyano compound IXby reaction of cyanophenol VII and haloisoxazole VIII.

The intermediate haloisoxazole VIII can be prepared as describedhereinbefore.

The intermediate phenols of formula IV can be prepared by reactingcyanophenol VII with hydroxylamine hydrochloride, using a proceduresimilar to that described hereinbefore for the preparation of amidoximeV from cyano compound IX, to give an amidoxime of the formula ##STR18##Amidoxime XIV is reacted with R₄ COX, (R₄ CO)₂ O, R₄ CO₂ H or ##STR19##using procedures similar to those described hereinbefore for thepreparation of compounds of formula I from amidoxime V, to give thecorresponding phenol of formula IV.

The compounds of formula I wherein R₁ is hydroxyalkyl, Y, R₂, and R₃ areas defined hereinbefore, and R₄ is dihalomethyl, trihalomethyl,cycloalkyl, alkoxyalkyl, 2,2,2-trifluoroethyl or amino and R₅ ishydrogen or lower alkyl can be prepared from a compound of the formula##STR20## wherein R₁ ' is tert-butyldimethylsilyloxyalkyl [(CH₃)₃CSi(Me)₂ --O--alkyl] and Y, R₂, R₃, R₄ and R₅ are as defined above inthis paragraph, by cleaving the tert-butyldimethylsilyl ether.

Cleavage of the tert-butyldimethylsilyl ether is carried out by treatingcompound XVII as defined above, with strong organic acid, e.g., aceticacid or trifluoroacetic acid, or inorganic acid, e.g., hydrochloric acidor sulfuric acid, in an inert solvent, e.g., tetrahydrofuran or dioxanein the presence of water at a temperature in the range of from about 20°to about 60° C.

The compound of formula XVII where R₄ is dihalo-methyl, trihalomethyl,cycloalkyl, alkoxyalkyl or 2,2,2-trifluoroethyl, can be prepared by aprocess which comprises reacting phenol IV wherein R₂ and R₃ are asdefined hereinbefore, R₅ is hydrogen or lower alkyl and R₇ is as definedabove in this paragraph for R₄, with an isoxazole of the formula##STR21## wherein R₁ ', Y and X₂ are as defined hereinbefore.

The phenol IV is reacted with haloisoxazole XVI using a proceduresimilar to that described hereinbefore for the preparation of cyanocompound IX from cyanophenol VII and haloisoxaozle VIII.

The phenol IV is reacted with isoxazole XV in the presence of diethylazodicarboxylate (DEAD) and triphenylphosphine in an inert solvent,e.g., tetrahydrofuran, chloroform, dimethylformamide orN-methylpyrrolidinone, at a temperature in the range of from about -20°to about 20° C.

The intermediate phenol IV can be prepared by the procedure describedhereinbefore.

The intermediate isoxazoles XV and XVI can be prepared by reactingisoxazole X, wherein R₁ is hydroxyalkyl, with tert-butyldimethylsilylchloride to give the corresponding tert-butyldimethylsilyl ether offormula ##STR22## where R₁ ' is as defined above, and R₅ is hydrogen orlower alkyl and reaction of an alkali metal derivative of compound XVIIIwith ethylene oxide or X₂ -Y'-X₂ respectively.

Isoxazole X, wherein R₁ is hydroxyalkyl, is reacted withtert-butyl(dimethyl)silyl chloride in the presence of 4(dimethylamino)pyridine and a base, e.g., triethylamine, pyridine orimidazole, in a dry inert solvent., e.g., methylene chloride, chloroformor tetrahydrofuran, at room temperature to give compound XVIII.Isoxazole XV is prepared by reacting an alkali metal derivative ofcompound XVIII with ethylene oxide, preferably in the presence of achelating agent, e.g., N,N,N',N'-tetramethylethylenediamine orhexamethyl phosphoric triamide, in a dry inert solvent, e.g.,tetrahydrofuran, at a temperature in the range of from about -78° toabout 20° C. The alkali metal derivative is prepared in situ by reactingcompound XVIII with an organo-alkali metal base, e.g., butyllithium orlithium diisopropylamide, under anhydrous conditions.

The compound of formula XVII, where R₄ is dihalomethyl, trihalomethyl,cycloalkyl, alkoxyalkyl or 2,2,2-trifluoroethyl, can also be prepared,as can the compound of that formula where R₄ is amino, according to thefollowing flow sheet: ##STR23##

The reaction of compound XV or XVI with cyanophenol VII to give compoundXIX is carried out by procedures similar to those described hereinbeforefor preparing compound XVII by reacting phenol IV with isoxazole XV orhaloisoxazole XVI respectively. The reaction of cyano compound XIX withhydroxylamine hydrochloride to give amidoxime XX, and the latter withthe acid halide, acid anhydride, carboxylic acid, cyanogen halide orketene 1,3-propanedithiol acetal to give compound XVII can be carriedout by procedures similar to those described hereinbefore for preparingamidoxime V from cyano compound IX and for preparing the compound offormula I from amidoxime V.

The compounds of formula I wherein R₁ is hydroxy, Y, R₂ and R₃ are asdefined hereinbefore, and R₄ is cycloalkyl or alkoxyalkyl can beprepared by reacting a compound of the formula ##STR24## where R₈ isalkyl and Y, R₂, R₃ and R₄ are as defined above in this paragraph, withhydroxylamine hydrochloride to give the compound of formula I where R₁is hydroxy.

Compound XXI is reacted with hydroxylamine hydrochloride in the presenceof a base, e.g., sodium hydroxide, and water in an alcoholic solvent,e.g., methyl or ethyl alcohol, at a temperature in the range of fromabout 0° to about 25° C.

The intermediate compounds of formula XXI can be prepared by reacting analkali metal derivative of compound III, wherein R₆ is as defined for R₄of compound XXI, with an alkyl haloformate, R₈ OCOX, where X is asdefined hereinbefore. The reaction takes place in a dry inert solvent,e.g., tetrahydrofuran or dioxane, at an initial temperature of about-78° to about -20° C. with subsequent warming to about 20° to about 25°C. The alkali metal derivative can be prepared in situ by reactingcompound III with an organo-alkali metal, e.g., butyllithium or lithiumdiisopropylamide, under anhydrous conditions.

Certain compounds of formula I are intermediates for other compounds offormula I as described hereinafter.

The acid halides, alkyl haloformates and acid anhydrides used in thehereinbefore described processes for preparing the compounds of formulaI and intermediates therefor, belong to well known classes of compoundsand can be readily prepared by known procedures.

The compound of formula I wherein R₁ is alkyl, trifluoromethyl,cycloalkyl or alkoxyalkyl, Y, R₂, R₃ are as defined hereinabove, and R₄is alkoxy or N=Q, where N=Q is alkylamino or dialkylamino, can beprepared from the corresponding compound of formula I wherein R₄ istrichloromethyl. In the case where R₄ is alkoxy, the trichloromethylcompound is reacted with an alkali metal alkoxide, e.g., sodiummethoxide or sodium ethoxide, and in the case where R₄ is N=Q, with anamine(N=Q), in a suitable solvent, e.g., dimethylformamide orN-methylpyrrolidinone, at room temperature to give the correspondingcompound of formula I where R₄ is alkoxy, alkylamino or dialkylamino.

The compounds of formula I wherein R₁ is hydroxyalkyl, Y, R₂ and R₃ areas defined hereinbefore, and R₄ is hydroxy, dihalomethyl, trihalomethyl,cycloalkyl, hydroxyalkyl, 2,2,2-trifluoroethyl or amino, can be preparedfrom the corresponding compound wherein R₁ is alkoxyalkyl by ethercleavage of the alkoxyalkyl moiety. The alkoxyalkyl compound is treatedwith trimethylsilyl iodide in a dry inert solvent, e.g.,1,2-dichloroethane, chloroform or acetonitrile, at a temperature in therange of from about 60° to about 80° C. to give the correspondinghydroxyalkyl compound.

The compounds of formula I wherein R₁ is alkyl, alkoxy, trifluoromethyl,cycloalkyl or alkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, andR₄ is CON=Q, where N=Q is amino, alkylamino or dialkylamino, can beprepared by reacting the corresponding compound of formula I wherein R₄is alkoxycarbonyl with amine N=Q in a polar solvent, e.g., ethyl alcoholor N-methylpyrrolidinone, at room temperature to give the correspondingcompound where R₄ is CON=Q.

The compound of formula I where R₁ is alkyl, alkoxy, trifluoromethyl,cycloalkyl or alkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, andR₄ is cyano, can be prepared from the corresponding compound wherein R₄is CON=Q, where N=Q is amino, by treating the latter withtrifluoroacetic anhydride in the presence of a base, e.g., pyridine ortriethylamine, in a dry inert solvent, e.g., tetrahydrofuran, chloroformor 1,2-dichloroethane, at a temperature in the range of from about 0° toabout 20° C.

The compounds of formula I wherein R₁ is alkoxy or hydroxyalkoxy, Y, R₂and R₃ are as defined above, and R₄ is alkoxy, trihalomethyl,cycloalkyl, alkoxyalkyl, 2,2,2-trifluoro-ethyl or dialkylamino, can beprepared by etherification of the corresponding compound of formula Iwherein R₁ is hydroxy. The etherification takes place by reacting thehydroxy compound with an alkyl halide or hydroxyalkyl halide, wherehalide is bromide, chloride or iodide, in the presence of a base, e.g.,potassium carbonate or sodium carbonate, in an inert dry solvent, e.g.,acetone, butanone or acetonitrile, at a temperature in the range of fromabout 50° to about 90° C.

The compounds of formula I wherein R₁ is alkyl, cycloalkyl,hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy, Y, R₂ and R₃ are as definedhereinbefore, and R₄ is hydroxyalkyl can be prepared bytransesterification of the corresponding compound of formula I whereinR₄ is alkanecarbonyloxyalkyl. The transesterification is carried out bytreating the alkanecarbonyloxyalkyl compound with an inorganic ororganic base, e.g., potassium carbonate, sodium bicarbonate ortriethylamine, in an alcoholic solvent, e.g., methyl or ethyl alcohol,at room temperature.

The compounds of formula I wherein R₁ is alkyl, cycloalkyl orhydroxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, and R₄ ishydroxyalkyl, can also be prepared by ether cleavage of thecorresponding compound of formula I wherein R₄ is alkoxyalkyl. The ethercleavage can be carried out by treating the alkoxy compound withtrimethylsilyl iodide using a procedure similar to that describedhereinbefore for preparing the compound of formula I wherein R₄ ishydroxyalkyl.

The compound of formula I wherein R₁ is alkyl, alkoxy, cycloalkyl,hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy, Y, R₂ and R₃ are as definedhereinbefore, and R₄ is iodomethyl, can be prepared from thecorresponding compound of formula I wherein R₄ is chloromethyl byreaction with alkali metal iodide, e.g., sodium iodide. The reactiontakes place by treating the chloromethyl compound with the alkali metaliodide, e.g., sodium or potassium iodide, in an inert solvent, e.g.,acetone or butanone, at about 20° C.

The compounds of formula I wherein R₁ is alkyl, alkoxy, cycloalkyl oralkoxyalkyl, Y, R₂ and R₃ are as defined hereinbefore, and R₄ is(4-methylphenyl)sulfonyloxymethyl, are prepared from the correspondingcompound of formula I wherein R₄ is hydroxymethyl by reaction with(4-methylphenyl)sulfonyl halide, where halide is bromide, chloride oriodide, in the presence of an inorganic base, e.g., potassium carbonateor sodium bicarbonate. The reaction takes place by reacting thereactants in an inert solvent, e.g., methylene chloride, chloroform or1,2-dichloroethane, at about 20° C.

Compounds of formula I wherein R₅ is halo may be prepared from compoundsof formula I wherein R₅ is hydrogen by standard halogenation methodsknown in the art; for example, addition of a halide, such as bromine ina suitable acid; glacial acetic acid for example, or other knownmethods.

Compounds of formula I wherein R₅ is alkyl may be prepared by alkylationof compounds of formula I where R₅ is hydrogen by known alkylationmethods, such as, for example, addition of strong base, and thenaddition of suitable alkyl halide giving a compound of formula I orother well known methods.

It may be desirable to block or mask functionality of other groupspresent in the molecule, known to be susceptible to undesiredhalogenation or alkylation side reactions such as, for example hydroxylower alkyl groups, carboxy groups, acetamido groups and the like, usingconventional means known in the art, but this is well within the scopeof practice of the skilled practitioner.

In the various processes described hereinabove for the preparation ofthe compounds of the invention, it will be appreciated that thereactions should be carried out for a time sufficient to provide thedesired product and that for any specific reaction type, the time of thereaction will depend upon one or more factors such as, e.g., the natureof the reactants, the solvent employed and/or the temperature at whichthe reaction is carried out.

Once prepared, the antiviral compounds of the invention are formulatedfor use by preparing a dilute solution or suspension in apharmaceutically acceptable aqueous, organic or aqueous-organic mediumfor topical or parenteral administration by intravenous or intramuscularinjection, or for intranasal or ophthalmic application; or are preparedin tablet, capsule, or aqueous suspension form with conventionalexcipients for oral administration. As such, the compositions are usefulin treating or preventing viral infection, especially picornaviralinfection.

The structures of the compounds of the invention were established bymodes of synthesis and elementary analysis, and by infrared, nuclearmagnetic resonance and/or mass spectra.

The invention is further illustrated but not limited by the followingexamples.

EXAMPLE 1

a) 3-(3-Methylisoxazol-5-yl)propyl alcohol.

3,5-Dimethylisoxazole (220 g, 2.27 moles) in 2.2 L tetrahydrofuran undernitrogen was cooled with stirring to -75° C. and 908 mL of 2.5Mn-butyllithium (2.27 moles) in hexanes were added over 1 hour keepingthe temperature at or less than 65° C. The chilled solution was stirredfor thirty minutes after addition was complete and was then treated atabout -70° C. with a solution of 112 g (2.54 moles) of ethylene oxide in390 ml tetrahydrofuran over a period of 1.5 hours, keeping thetemperature at about -65° C. and stirred overnight. The mixture at 8° C.was quenched with continued cooling in an 8° C. bath by adding 1.2 L of2.5M hydrochloric acid over a period of 20 minutes, during which timethe temperature rose to 23° C., and was stirred for 10 minutes. Theorganic phase was separated, washed with 500 ml of water andconcentrated to give 147 g of title compound as a brown oil. Thecombined aqueous phases (original+wash phase) were extracted with methyltert-butyl ether (3×200 ml) and the combined organic extracts wereconcentrated to give an additional 125 g of title compound as a brownoil.

b) 3-(3-Methylisoxazol-5-yl)propyl chloride.

To the product from part (a) (125 g, 0.885 mole) in 1225 ml methylenechloride was added 192 ml (2.63 moles) of thionyl chloride over a periodof 1 hour during which time the temperature rose to 40° C. to a gentlereflux. Heating at reflux was continued for 3 hours, the reactionmixture was allowed to stand overnight, and then heating at reflux wascontinued for 1 hour. The reaction mixture was added as a steady streamto 3 kg of ice water with vigorous stirring, stirring was continued for1 hour and the aqueous phase was separated. Water (1 L) was added to theorganic phase followed by 161 g of solid sodium bicarbonate in portionswith vigorous stirring. The organic phase was separated and concentratedin vacuo to give a black oil which was purified by wipe-filmdistillation to give 94 g of the title compound as a yellow oil, bp 65°C./0.09 mm.

c) 3,5-Dimethyl-4-[3-(3-methylisoxazol-5-yl)propyloxy]benzo-nitrile.

A mixture of 3,5-dimethyl-4-hydroxybenzonitrile (7.36 g, 50.0 mmol), dryN-methylpyrrolidinone (100 mL), milled potassium carbonate (13.8 g, 100mmol), potassium iodide (0.84 g, 5.0 mmol), and the product from part(b) (12.0 g, 75.0 mmol) was stirred at 60° C. for 18 hours. Aftercooling to room temperature, the mixture was partitioned between 200 mLwater and 100 mL ethyl acetate. The aqueous layer was extracted twicewith 50 mL portions of ethyl acetate. The combined organic extracts werewashed with water, brine, dried (MgSO₄), and concentrated in vacuo toprovide 18.3 g of a yellow oil. MPLC (Silica Gel 60 50×460 mm, 25% ethylacetate in hexanes) provided 12.7 g (94.1%) of pure title compound as awhite solid, m.p. 46°-48° C. (methanol).

d)3,5-Dimethyl-4-[3-(3-methylisoxazol-5-yl)propyloxy]-N-hydroxybenzenecarboximidamide.

A mixture of the product prepared according to part (c) (18.4 g, 68.1mmol), absolute ethanol (200 mL), milled potassium carbonate (46.9 g,0.340 mol), and hydroxylamine hydrochloride (23.6 g, 0.340 mol) wasrefluxed for 18 hours. The hot mixture was filtered and the solidsremaining washed with hot ethanol. The combined filtrates wereconcentrated in vacuo to provide 19.4 g (93.9%) of the title compound asa white powder which was of sufficient purity to be used in subsequentsteps. A sample was recrystallized from ethanol to give a white solid,m.p. 129°-130.5° C.

e)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅ =hydrogen].

To a solution of the product from part (d) (4.38 g, 14.4 mmol) in 8.0 mLdry pyridine was added 4.07 mL (28.8 mmol) of trifluoroacetic anhydrideat a rate to maintain a gentle reflux. After addition was complete, themixture was allowed to cool to room temperature, and diluted with water.The solids obtained were washed with water, dried in vacuo, and purifiedby chromatography (Silica Gel 60, 15-40% ethyl acetate in hexanes), togive 4.76 g of pure title compound as a white solid, m.p. 61°-62° C.

EXAMPLE 2

a) 3,5-Difluoro-4-hydroxybenzonitrile.

A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I)cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxedfor 6 hours, cooled to room temperature, diluted with water (150 mL),and filtered. The tan solids obtained were washed with water andretained. The combined filtrates were acidified (IN HCl) and extractedwith ethyl acetate. The combined organic extracts were dried (MgSO₄),concentrated in vacuo, and purified by flash chromatography (Silica Gel60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compoundas an off-white solid, mp 195°-197° C.

The tan solid was suspended in ethyl acetate with a small amount ofacetone, filtered, and concentrated in vacuo. The residue obtained waspartitioned between ethyl acetate and 1N HCl. The aqueous phase wasextracted with ethyl acetate and the combined organic phases purified asabove to provide an additional 0.43 g (49% combined yield) of pure titlecompound.

The following compounds were prepared by a procedure similar to that ofExample 1(c):

    ______________________________________                                        Example   Compound                                                            ______________________________________                                        2b        3,5-Difluoro-4-[3-(3-methylisoxazol-5-                                        yl)propyl-oxy]benzonitrile, mp 23-24.5° C.                             (ether/hexanes) - prepared from 3,5-difluoro-                                 4-hydroxybenzonitrile and the product of                                      Example 1b; yield 49.1%.                                            3a        3,5-Dichloro-4-[3-(3-methylisoxazol-5-                                        yl)propyl-oxy]benzonitrile, mp 69.5-70.5° C.                           (methanol) (white solid) - prepared from 3,5-                                 dichloro-4-hydroxy-benzonitrile and the                                       product of Example 1b; yield 80.7%.                                 ______________________________________                                    

The following compounds were prepared by a procedure similar to that ofExample 1d:

    ______________________________________                                        Example                                                                              Compound                                                               ______________________________________                                        2c     3,5-Difluoro-4-[3-(3-methylisoxazol-5-yl)propyl-oxy]-                         N-hydroxybenzenecarboximidamide, mp 122-124° C. -                      prepared from the product of Example 2b; yield 86%.                           The crude product was purified by suspension in 10%                           ethanol in chloroform, filtration, concentration in                           vacuo and trituration of the resulting white solid in                         cold chloroform.                                                       3b     3,5-Dichloro-4-[3-(3-methylisoxazol-5-yl)propyl-oxy]-                         N-hydroxybenzenecarboximidamide - pre-pared from                              the product of Example 3a (0.5 g). The product                                (0.78 g), obtained on concentration of the filtrates                          as an oily solid, was used in the next step.                           ______________________________________                                    

The following compounds were prepared by a procedure similar to that ofExample 1e:

    ______________________________________                                        Example                                                                              Compound                                                               ______________________________________                                        2d     5-{3-[2,6-Difluoro-4-(5-trifluoromethyl-1,2,4-oxadiazol-                      3-yl)phenoxy]propyl}-3-methylisoxazole [I; R.sub.1 = CH.sub.3,                Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 = 2,6-(F).sub.2, R.sub.4            = CF.sub.3,                                                                   R.sub.5 = hydrogen], mp 36-37° C. (hexanes) (white                     solid) - from the product of Example 2c and trifluoro-                        acetic anhydride; yield 44.5%.                                         3c     5-{3-[2,6-Dichloro-4-(5-trifluoromethyl-1,2,4-oxadiazol-                      3-yl)phenoxy]propyl}-3-methylisoxazole [I; R.sub.1 = CH.sub.3,                Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 = 2,6-(Cl).sub.2,                   R.sub.4 = CF.sub.3,                                                           R.sub.5 = hydrogen], mp 65-67° C. (hexanes) (white                     solid) - from the product of Example 3b and trifluoro-                        acetic anhydride; yield 80.5%.                                         4      5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-                             dimethylphenoxy]propyl}-3-methylisoxazole [I; R.sub.1 =                       CH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3                           = 2,6-(CH.sub.3).sub.2,                                                       R.sub.4 = cyclo-propyl, R.sub.5 = hydrogen), mp 85-88° C.              (methanol) (white solid) - from the product of                                Example 1d and cyclopropane-carbonyl chloride;                                yield 71.0%.                                                           5      5-{3-[2,6-Dimethyl-4-(5-methoxymethyl-1,2,4-oxadiazol-                        3-yl)phenoxy]propyl}-3-methylisoxazole [I; R.sub.1 =                          CH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3                           = 2,6-(CH.sub.3).sub.2,                                                       R.sub.4 = CH.sub.2 OCH.sub.3, R.sub.5 = hydrogen], mp                         63-64° C.                                                              (ether/hexane) (white solid) - from the product of                            Example 1d and methoxy-acetyl chloride; yield 76.1%.                   6      5-{3-[2,6-Dimethyl-4-(5-fluoromethyl-1,2,4-oxadiazol-3-                       yl)phenoxy]propyl}-3-methylisoxazole [I; R.sub.1 = CH.sub.3,                  Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 = 2,6-(CH.sub.3).sub.2,             R.sub.4 =                                                                     CH.sub.2 F, R.sub.5 = hydrogen], mp 80-80.5° C. (methanol)             (white solid) - from the product of Example 1d and                            fluoroacetyl chloride; yield 45.6%.                                    7      5-{3-[2,6-Dimethyl-4-(5-ethoxycarbonyl-1,2,4-oxadiazol-                       3-yl)phenoxy]propyl}-3-methylisoxazole [I; R.sub.1 = CH.sub.3,                Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 = 2,6-(CH.sub.3).sub.2,             R.sub.4 =                                                                     CO.sub.2 CH.sub.2 CH.sub.3, R.sub.5 = hydrogen], mp                           105-106° C.                                                            (ethyl acetate/hexane) (white solid) - from the product                       of Example 1d and ethyl oxalyl chloride; yield 67.8%.                  ______________________________________                                    

EXAMPLE 8

5-{3-[2,6-Dimethyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[tautomer of I where R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =OH,R₅ =hydrogen].

To a chilled (0° C.) suspension of the product from Example 1d (3.03 g,10.0 mmol), dry acetone (30 mL) and finely divided potassium carbonate(1.52 g, 11 mmol) was added dropwise a solution of ethyl chloroformate(1.05 mL, 11.0 mmol) in acetone (5.5 mL). After stirring at 0° C. for 1hour, the reaction mixture was diluted with water (100 mL) and extractedwith methylene chloride (3×25 mL). The combined organic extracts werewashed with brine, dried (MgSO₄), filtered through a short column ofFlorisil, and concentrated in vacuo to give the crude intermediateO-acyl derivative as an off-white solid which was then heated at120°-130° C. for 45 minutes to give the title compound (2.38 g, 75.4%),mp -194°-195° C. (methanol) (white needles).

The following compounds were prepared by a procedure similar to that ofExample 8:

    ______________________________________                                        Example                                                                              Compound                                                               ______________________________________                                         9     5-{3-[2,6-Dimethyl-4-(5-methylcarbonyloxy-methyl-                             1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole                        [I; R.sub.1 = CH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3             = 2,6-                                                                        (CH.sub.3).sub.2, R.sub.4 = CH.sub.2 OCOCH.sub.3, R.sub.5 =                   hydrogen], mp                                                                 71-73° C. (ether/-hexanes) (white solid) - from                        the product of Example 1d and acetoxyacetyl chloride;                         yield 71.3%. The crude product was purified by                                chromatography (Silica Gel 60, 35% ethyl acetate in                           hexanes).                                                              10     5-{3-[4-(5-Chloromethyl-1,2,4-oxadiazol-3-yl)-                                2,6-dimethylphenoxy]propyl}-3-methylisoxazole                                 [I; R.sub.1 = CH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3             = 2,6-                                                                        (CH.sub.3).sub.2, R.sub.4 = CH.sub.2 Cl, R.sub.5 = hydrogen], mp              75-76° C.                                                              (methanol) (white solid) - from the product of                                Example 1d and chloroacetyl chloride. The crude                               product was purified by chromatography (Silica Gel                            60, 20% ethyl acetate in hexanes); yield 76.2%.                        11     5-{3-[2,6-Dimethyl-4-(5-(l-methylcarbonyloxy-                                 ethyl)-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-                                methylisoxazole [I; R.sub.1 = CH.sub.3, Y = (CH.sub.2).sub.3,                 R.sub.2 and                                                                   R.sub.3 = 2,6-(CH.sub.3).sub.2, R.sub.4 = CH(CH.sub.3)OCOCH.sub.3,            R.sub.5 =                                                                     hydrogen], mp 77-77.5° C. (white solid) - from the                     product of Example 1d and 2-acetoxypropionyl                                  chloride; yield 64.6%.                                                 ______________________________________                                    

EXAMPLE 12

5-{3-[2,6-Dimethyl-4-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CCl₃, R₅ =hydrogen].

Trichloroacetic acid (22.8 g, 140 mmol) was added to the product ofExample 1d (10.6 g, 34.8 mmol) and heated at 85° C. until a thicksolution was obtained. Trichloroacetyl chloride (14.5 mL, 69.6 mmol) wasadded in three equal portions. A vigorous reaction ensued after additionof the first portion. The mixture was heated an additional hour at 94°C. The cooled mixture was diluted with water and extracted with ethylacetate (3×25 mL). The combined organic phases were washed withsaturated sodium bicarbonate, brine, dried (MgSO₄) and concentrated invacuo to give 10.1 g of orange oil. Chromatography (Silica Gel 60,methylene chloride) provided 6.94 g of yellow oil which was crystallizedfrom methanol to give 5.03 g of pure title compound as white needles, mp77°-77.5° C.

EXAMPLE 13

5-{3-[4-(5-Dichloromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CHCl₂, R₅ =hydrogen].

Dichloroacetic acid (1.24 mL, 15.0 mmol) was added to the product ofExample 1d (1.14 g, 3.76 mmol) and heated at 85° C. until a solution wasobtained. Dichloroacetic anhydride (1.14 mL, 7.52 mmol) was addeddropwise rapidly and stirred at 85° C. for an additional hour. Work-upas described for Example 12 provided 1.51 g of yellow-brown oil whichwas purified by chromatography (Silica Gel 60, 25% ethyl acetate inhexanes) to give 1.37 g (91.3%) of pure title compound as a pale yellowoil which solidified upon standing, mp 52°-3° C. (ethanol).

EXAMPLE 14

5-{3-[4-(5-Difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =CHF₂, R₅ =hydrogen).

Difluoroacetic acid (0.31 mL, 5.0 mmol) was added to a cold (-25° C.)solution of 1,1'-carbonyldiimidazole (0.80 g, 5.0 mmol) in drytetrahydrofuran (5.0 mL). After 5 minutes, the resulting suspension wasadded dropwise rapidly to a solution of the product of Example 1d in drytetrahydrofuran (20 mL). The mixture was refluxed for 2 hours, cooled,diluted with water, and extracted with ethyl acetate (3×). The combinedorganic phases were washed with water, brine, dried (MgSO₄), andconcentrated in vacuo to give 0.78 g of a pale yellow solid.Chromatography (Silica Gel 60, 30% ethyl acetate in hexanes) provided0.55 g of pure title compound as a pale yellow oil which solidified uponstanding, mp 70.5°-71° C. (methanol).

EXAMPLE 15

5-{3-[4-(5-Imino-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-methylisoxazole[tautomer of I where R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =NH₂,R₅ =hydrogen].

Cyanogen bromide (1.17 g, 11.0 mmol) was added in portions to a mixtureof the product of Example 1d (3.03 g, 10.0 mmol) and potassiumbicarbonate (1.10 g, 11.0 mmol) in 50% aqueous ethanol (8.0 mL). After15 minutes, the thick yellow suspension was diluted with water andfiltered. The yellow solid obtained was washed with water and ether togive 1.48 g (45.1%) of pure title compound as a yellow powder, mp175°-183° C.

EXAMPLE 16

5-{3-[2,6-Dimethyl-4-(5-methoxy-1,2,4-oxadiazol-3-yl)phen-oxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃ R₂ and R₃ =2,6-(CH₃)₂, R₄ =OCH₃ R₅ =hydrogen].

The product of Example 12 (627 mg, 1.46 mmol) was added to a freshlyprepared solution of sodium methoxide in methanol (1.5 equivalentssodium in 5 mL methanol) in dry dimethylformamide (3-5 mL) and themixture was stirred at room temperature for 15-30 minutes. The reactionmixture was diluted with water and extracted with ethyl acetate (3×).The combined organic extracts were washed with water, brine, dried(MgSO₄) and concentrated in vacuo. The crude residue (0.64 g) waspurified by chromatography (Silica Gel 60, first with 2% methanol inmethylene chloride followed by 5% ethyl acetate in methylene chloride)to give pure title compound (308 mg) as a colorless oil whichcrystallized from methanol, mp 64.5°-65.5° C. (white solid).

EXAMPLE 17

5-{3-[2,6-Dimethyl-4-(5-ethoxy-1,2,4-oxadiazol-3-yl]phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃ R₂ and R₃ =2,6-(CH₃)₂, R₄ =OCH₂ CH₃ R₅ =hydrogen].

Following the procedure of Example 16 but using sodium ethoxide inethanol in place of sodium methoxide in methanol there was obtained fromthe product of Example 12 (905 mg, 2.10 mmol) a crude residue (0.82 g)which was purified by chromatography (Silica Gel 60, 2% ethyl acetate inmethylene chloride) to give 0.52 g (69%) of pure title compound as ayellow solid, mp 70°-72.5° C. (ethanol).

EXAMPLE 18

5-{3-[2,6-Dimethyl-4-(5-methylimino-4.5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[tautomer of I where R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄=NHCH₃, R₅ =hydrogen].

The product of Example 12 (1.00 g, 2.32 mmol) was added to 5 ml of 40%aqueous methylamine in dimethylformamide (3-5 mL) and the mixture wasstirred at room temperature for 18 hours. The reaction mixture wasdiluted with water and extracted with ethyl acetate (3×). The combinedorganic extracts were washed with water, brine, dried (MgSO₄) andconcentrated in vacuo. The crude residue (0.54 g) was purified bychromatography (Silica Gel 60, first with 2% methanol in methylenechloride and then with 50% ethyl acetate in hexanes) to give 300 mg(37.5%) of pure title compound as a yellow solid, mp 126.5°-127° C.(ethanol).

EXAMPLE 19

5-{3-[2,6-Dimethyl-4-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-phenoxy]propyl)-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =N(CH₃)₂, R₅=hydrogen].

Following the procedure of Example 18 but using 40% aqueousdimethylamine in place of 40% aqueous methylamine and reducing thereaction time to 15-30 minutes, there was obtained from the product ofExample 12 (0.97 g, 2.2 mmol) a crude residue (0.75 g) which waspurified by chromatography (Silica Gel 60, 50% ethyl acetate/hexanes) togive 0.70 g (84%) of pure title compound as a pale yellow solid, mp123°-124° C. (ethanol).

EXAMPLE 20

a) 3,5-Dimethyl-4-(3-ethinylpropoxy)benzonitrile.

Following the procedure of Example 1c and using 14.7 g (100 mmol) of3,5-dimethyl-4-hydroxybenzonitrile and substituting 5-chloro-1-pentyne(12.7 mL, 120 mmol) for the product of Example 1b, there was obtained ared-brown oil which was purified by chromatography (Silica Gel 60, 15%ethyl acetate in hexanes) to give pure title compound (21.2 g, 99.4%) asa pale yellow oil.

b) 3,5-Dimethyl-4-(3-ethinylpropoxy)-N-hydroxybenzene-carboximidamide.

Following the procedure of Example 1d and using 13.0 g (61.0 mmol) ofthe product from part (a), there was obtained the title compound (14.9g, 99.3%) as a white solid which was sufficiently pure for use in thenext step.

c)3-[3,5-Dimethyl-4-(3-ethinylpropoxy)phenyl]-5-trifluoromethyl-1,2,4-oxadiazole.

Following the procedure of Example 1e and using 7.40 g (30.0 mmol) ofthe product of part (b), 9.0 mL of dry pyridine and 8.50 mL oftrifluoroacetic anhydride there was obtained pure title compound (6.42g, 65.9%) as a pale yellow oil which crystallized from methanol to givethe title compound as a white solid, mp 45.5°-48° C.

Procedure 1--general procedure for preparing the compounds of Examples21, 22, 23, 28a and 29a below

To a solution of N-chlorosuccinimide (NCS, 1.8-2.5 equivalents) in dryN,N-dimethylformamide or N-methylpyrrolidinone (1.6-3.0 mL per mmol NCS)and 1-2 drops of pyridine was added dropwise a solution of oxime(1.8-2.5 equivalents) in the same solvent (0.40-0.80 mL per mmol oxime).The internal temperature was maintained at 25°-30° C. with a 25° C.water bath. After 1 hour at room temperature, a solution of theappropriate ethinyl compound (formula III or XII) (1 equivalent) in thesame solvent (0.80 mL per mmol the ethinyl compound) was added. Thereaction mixture was heated to 85°-90° C. and a solution oftriethylamine (TEA, 1.8-2.5 equivalents) in the same solvent (0.80-1.6mL per mmol TEA) was added dropwise over 45-90 minutes. After anadditional hour at 85°-90° C., the mixture was cooled to roomtemperature, diluted with water, and extracted with ethyl acetate (3×).The combined organic phases were washed with 10% KHSO₄, water, brine,dried (MgSO₄ or Na₂ SO₄) and concentrated in vacuo. The crude productwas purified by chromatography (Silica Gel 60, 15-40% ethyl acetate inhexanes).

The following compounds were prepared by Procedure 1:

    ______________________________________                                        Example                                                                              Compound                                                               ______________________________________                                        21     5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-                                oxadiazol-3-yl)phenoxy]propyl}-3-(methoxymethyl)-                             isoxazole [I; R.sub.1 = CH.sub.2 OCH.sub.3, Y = (CH.sub.2).sub.3,             R.sub.2                                                                       and R.sub.3 = 2,6-(CH.sub.3).sub.2, R.sub.4 = CF.sub.3, R.sub.5 =             hydrogen],                                                                    colorless oil (yield 70.1%) - from the product of                             Example 20c (2.00 g, 6.17 mmol) and methoxyacetal-                            dehyde oxime (1.10 g, 12.3 mmol).                                      22     5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-                                oxadiazol-3-yl)phenoxy]propyl}-3-(ethoxymethyl)-                              isoxazole [I; R.sub.1 = CH.sub.2 OCH.sub.2 CH.sub.3, Y                        = (CH.sub.2).sub.3, R.sub.2                                                   and R.sub.3 = 2,6-(CH.sub.3).sub.2, R.sub.4 = CF.sub.3, R.sub.5 =             hydrogen],                                                                    mp 24-25° C. (methanol) (white powder) (yield                          35.3%) - from the product of Example 20c (2.00 g,                             6.17 mmol) and 2-ethoxyacetaldehyde oxime (1.27 g,                            12.3 mmol).                                                            23     3-Cyclopropyl-5-{3-[2,6-dimethyl-4-(5-trifluoromethyl-                        1,2,4-oxadiazol-3-yl)phenoxy]propyl}-isoxazole [I;                            R.sub.1 = cyclopropyl, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 =            2,6-                                                                          (CH.sub.3).sub.2, R.sub.4 = CF.sub.3, R.sub.5 = hydrogen), mp                 63.5-65° C.                                                            (ethanol) (white needles) (yield 82%) - from the                              product of Example 20c (0.92 g, 2.8 mmol) and cyclo-                          propylcarboxaldehyde oxime (0.48 g, 5.6 mmol).                         ______________________________________                                    

2=Ethoxyacetaldehyde oxime (used in Example 22 above)

A solution of hydroxylamine hydrochloride (18.8 g, 0.270 mol), ethanol(25 mL), water (40 mL) and 1,1,2-triethoxyethane was warmed at 45° C.for 30 minutes, cooled to room temperature, and extracted with ether(3×). The combined organic phases were dried (MgSO₄), concentrated invacuo, and filtered through a small plug of cotton to give 10.1 g oftitle compound as a pale yellow oil which was used as is.

EXAMPLE 24

5-Cyclopropyl-3-[3,5-dimethyl-4-(3-ethinylpropoxy}phenyl]-1,2,4-oxadiazole.

Following the procedure of Example 1e and using 5.00 g (20.3 mmol) ofthe product of Example 20b, 75 mL of dry pyridine and 2.77 mL (30.5mmol) of cyclopropylcarbonyl chloride there was obtained pure titlecompound (3.98 g, 66.2%) as a nearly colorless oil which solidified onstanding, mp 45°-46° C. (methanol).

Procedure 2--general procedure for preparing the compounds of Examples25, 26 and 27 below

To a chilled (0° C.) solution of the appropriate aldehyde oxime (2.5equivalents) in dry dimethylformamide (DMF) (15 mL) was added in 1portion N-chlorosuccinimide (NCS) (2.5 equivalents). After 1-2 hours,the product from Example 24 (1 equivalent) was added and the wholeheated to 80° C. A solution of triethylamine (2.5 equivalents) in dryDMF (5 mL) was added dropwise over 90 minutes. The mixture was heated anadditional 18 hours. Work up and purification as described for Example21 provided the pure product.

The following compounds were prepared by Procedure 2:

    ______________________________________                                        Example                                                                              Compound                                                               ______________________________________                                        25     5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-                             dimethylphenoxy]propyl}-3-ethylisoxazole [I;                                  R.sub.1 = CH.sub.2 CH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2 and                R.sub.3 = 2,6-                                                                (CH.sub.3).sub.2, R.sub.4 = cyclopropyl, R.sub.5 = hydrogen],                 colorless                                                                     oil - from the product of Example 24 and propional-                           dehyde oxime; yield 67%.                                               26     5-{3-[5-(Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-                               dimethylphenoxy]propyl}-3-methoxymethyl)-isoxazole                            [I; R.sub.1 = CH.sub.2 OCH.sub.3, Y = (CH.sub.2).sub.3, R.sub.2               and R.sub.3 = 2,6-                                                            (CH.sub.3).sub.2, R.sub.4 = cyclopropyl, R.sub.5 = hydrogen],                 mp 44-45° C. (methanol) (white solid) - from the                       product of Example 24 and methoxyacetaldehyde                                 oxime; yield 26.1% (from combination of two runs).                     27     3-Cyclopropyl-5-{3-[5-(cyclopropyl-1,2,4-oxadiazol-                           3-yl)-2,6-dimethylphenoxy]propyl}isoxazole [I; R.sub.1 =                      R.sub.4 = cyclopropyl, Y = (CH.sub.2).sub.3, R.sub.2 and R.sub.3 =            2,6-                                                                          (CH.sub.3).sub.2 ], mp 59-60° C. (methanol) (white solid)              -                                                                             from the product of Example 24 and cyclopropyl-                               carboxaldehyde oxime; yield 60.4%.                                     ______________________________________                                    

EXAMPLE 28

a) 3,5-Dimethyl-4-[3-(3-ethylisoxazol-5-yl)propyloxy]benzo-nitrile.

Following Procedure 1 above but omitting the pyridine and usingpropionaldehyde oxime (8.6 g, 118 mmol) and the product of Example 20a(10.1 g, 47.0 mmol) there was obtained 4.90 g (36.7%) of pure titlecompound, mp 53.5°-54.5° C. (ethanol).

b)3,5-Dimethyl-4-[3-(3-ethylisoxazol-5-yl)propyloxy]-N-hydroxybenzenecarboximidamide.

A mixture of the product from part (a) (2.01 g, 7.50 mmol), ethanol (20mL), hydroxylamine hydrochloride (2.61 g, 37.5 mmol), and finely dividedpotassium carbonate (5.20 g, 37.5 mmol) was refluxed for 18 hours. Themixture was filtered hot, the filter cake washed with ethanol, and thecombined filtrates concentrated in vacuo to give 2.57 g of crude titlecompound as a pasty yellow solid, which was used as such in the nextstep.

c)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-ethylisoxazole[I; R₁ =CH₂ CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅=hydrogen].

All the product from part (b) was dissolved in pyridine (2.3 mL) andtrifluoroacetic anhydride (2.1 mL, 15 mmol) was added dropwise. Themixture was refluxed for 1 hour, cooled to room temperature, dilutedwith water, and extracted with methylene chloride (3×). The combinedorganic phases were washed with IN HCl, water, brine, dried (MgSO₄), andconcentrated in vacuo. The pale yellow oil obtained (2.15 g) waschromatographed (Silica Gel 60, methylene chloride) to give 2.10 g(70.7%) of pure title compound as a white solid, mp 157°-158° C.(methanol).

EXAMPLE 29

a)3,5-Dimethyl-4-{3-[3-(2-methoxyethyl)isoxazol-5-yl]propyloxy}benzonitrile.

Following Procedure 1 above and using 3-methoxypropionaldehyde oxime(1.94 g, 18.8 mmol) and the product of Example 20a (2.20 g, 10.3 mmol)there was obtained 1.51 g (46.5%) pure title compound as a colorless oilwhich crystallized from ethanol as fine white needles, mp 64°-64.5° C.There was recovered 0.89 g (40.4%) of starting product of Example 20a.

b)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-(methoxyethyl)isoxazole[I; R₁ =CH₂ CH₂ OCH₃, Y=(CH₂)₃, R₄ =CF₃, R₅ =hydrogen].

Sodium (442 mg, 19.2 mmol) was dissolved in dry methanol (20 mL)contained in an addition funnel. This solution was added dropwise to asolution of hydroxylamine hydrochloride (1.34 g, 19.2 mmol) in drymethanol (10 mL). A fine white precipitate formed. After 1 hour, asolution of the product from part (a) (1.21 g, 3.85 mmol) in drymethanol (5 mL) was added and the mixture heated at reflux for 2.5hours. The hot reaction mixture was filtered, the filter cake washedwith methanol, and the combined filtrates concentrated in vacuo. Thewhite oily solid obtained was dissolved in pyridine (4 mL) andtrifluoroacetic anhydride (1.63 mL, 11.6 mmol) was added at a rate tomaintain a gentle reflux. The mixture was heated at reflux for anadditional 30 minutes, cooled to room temperature, diluted with water,and extracted with ethyl acetate (3×). The combined organic phases werewashed with 10% KHSO₄, water, brine, dried (MgSO₄), and concentrated invacuo to give 2.27 g of yellow oil. Chromatography (Silica Gel 60, 30%ethyl acetate in hexanes) provided 1.28 g (78.0%) of pure title compoundas a colorless oil. Crystallization from methanol gave a white solid, mp36.5°-37° C.

3-Methoxypropionaldehyde oxime (used in Example 29a above)

To a solution of hydroxylamine hydrochloride (2.80 g, 40.2 mmol), 10%aqueous sodium acetate (4.0 mL) and water (6 mL) was added1,1,3-trimethoxypropane (2.12 mL, 14.9 mmol) and heated at 40°-50° C.for 30 minutes. After cooling to room temperature, the solution wassaturated with sodium chloride and extracted with ether (3×) andmethylene chloride (3×). The combined organic phases were dried (MgSO₄),filtered through a pad of Florisil, and concentrated in vacuo to provide1.6 g of title compound as a colorless oil which was used as is.

Procedure 3--general procedure for the preparation of the compounds ofExamples 30a and b, 31a and b, and 32a and b

A mixture of the appropriate 4-hydroxybenzonitrile (1 equivalent), dryethanol (3.7-8.9 mL per mmol of the 4-hydroxybenzonitrile),hydroxylamine hydrochloride (5 equivalents), and finely dividedpotassium carbonate (5 equivalents) was refluxed with efficient stirringfor 18 hours. The hot reaction mixture was filtered and the filter cakewashed with ethanol. The combined filtrates were concentrated in vacuoto give the crude amidoximes which were dissolved into pyridine (1-2 mLper mmol of the 4-hydroxybenzonitrile). Trifluoroacetic anhydride (5equivalents) was added at a rate to maintain a gentle reflux. Afterheating an additional 0.5-3 hours, the cooled reaction mixture wasdiluted with ethyl acetate and water (4:1) until homogeneous. Theorganic phase was extracted with cold 1N KOH (3×). The basic extractswere acidified with concentrated HCl and extracted with ethyl acetate(3×). The combined organic phases were washed with brine, dried (MgSO₄),concentrated in vacuo. Chromatography (Silica Gel 60, ethyl acetate inhexanes or Florisil, methylene chloride) provided the pure4-hydroxyphenyl-5-trifluoro-methyl-1,2,4-oxadiazole.

Following Procedure 3 there were prepared the following crudeintermediate amidoximes and corresponding4-hydroxy-5-trifluoromethyl-1,2,4-oxadiazoles:

    ______________________________________                                        Example Compound                                                              ______________________________________                                        30a     3,5-Dimethyl-4,N-dihydroxybenzenecarboximid-                                  amide - from 3,5-dimethyl-4-hydroxybenzonitrile.                      30b     3-(3,5-Dimethyl-4-hydroxyphenyl)-5-trifluoro-                                 methyl-1,2,4-oxadiazole, mp 114-115° C. (hexane)                       (white needles) - from the product of Example                                 30a; yield 75.2%.                                                     31a     3,5-Dichloro-4,N-dihydroxybenzenecarboximid-                                  amide - from 3,5-dichloro-4-hydroxybenzonitrile.                      31b     3-(3,5-Dichloro-4-hydroxyphenyl)-5-trifluoro-                                 methyl-1,2,4-oxadiazole, mp 96-98° C. (hexane)                         (white needles) - from the product of Example                                 31a; yield 52.0%.                                                     32a     4,N-Dihydroxybenzenecarboximidamide - from                                    4-hydroxybenzonitrile.                                                32b     3-(4-Hydroxyphenyl)-5-trifluoromethyl-1,2,4-                                  oxadiazole, mp 74-75° C. (hexanes) (white                              needles) - from the product of Example 32a;                                   yield 56.4%.                                                          ______________________________________                                    

EXAMPLE 30c

5-{5-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-phenoxy]pentyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₅, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅ =hydrogen].

Following a procedure similar to that of Example 1c but substituting theproduct from Example 30b (1.0 g, 3.9 mmol) for3,5-dimethyl-4-hydroxybenzonitrile and 5-(3-methylisoxazol-5-yl)pentylbromide (1.0 g, 4.3 mmol) for 3-(3-methylisoxazol-5-yl)propyl chlorideand using 0.72 g (4.3 mmol) of potassium iodide there was obtained 0.25g (16%) of pure title compound as a white solid, mp 41°-42° C.(methanol).

EXAMPLE 31c

5-{5-[2,6-Dichloro-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-phenoxy]pentyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₅, R₂ and R₃ =2,6-(Cl)₂, R₄ =CF₃, R₅ =hydrogen].

Following a procedure similar to that of Example 1c but substituting theproduct from Example 31b (0.93 g, 3.1 mmol) for3,5-dimethyl-4-hydroxybenzonitrile and 5-(3-methylisoxazol-5-yl)pentylbromide (1.0 g, 4.3 mmol) for 3-(3-methylisoxazol-5-yl)propyl chlorideand using 0.72 g (4.3 mmol) of potassium iodide there was obtained 0.83g (60%) of pure title compound as a white solid, mp 42°-43° C.(hexanes).

EXAMPLE 32c

3-Methyl-5-{3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-phenoxy]propyl}isoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ =R₃ =H, R₄ =CF₃, R₅ =hydrogen].

Following a procedure similar to that of Example 1c but substituting theproduct of Example 32b (0.42 g, 1.8 mmol) for3,5-dimethyl-4-hydroxybenzonitrile and using 0.63 g (4.0 mmol) of theproduct of Example 1b and 0.67 g (4.0 mmol) of potassium iodide therewas obtained, after trituration in cold methanol, 0.48 g (76%) of puretitle compound as a white powder, mp 68°-69° C. (methylenechloride-hexanes).

EXAMPLE 33

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazo-3-yl)-phenoxy]propyl}-3-(2-hydroxyethyl)isoxazole[I; R₁ =CH₂ CH₂ OH, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅=hydrogen].

A solution of the product of Example 29b (1.28 g, 3.00 mmol), dry1,2-dichloroethane (9 ml), and trimethylsilyl iodide (1.71 mL, 12.0mmol) was refluxed for 4 hours. To the cooled reaction mixture was addedmethanol (8 mL). The mixture was diluted with water and extracted withethyl acetate (3×). The combined organic phases were washed with 10%NaHSO₃, saturated NaHCO₃, brine, dried (MgSO₄), and concentrated invacuo. Chromatography (Silica Gel 60, 50% ethyl acetate in hexanes)provided 1.11 g (90.2%) of pure title compound as a colorless oil whichsolidified upon standing, mp 74.5°-75° C. (methanol)(white solid).

EXAMPLE 34

a) 3-(tert-butyldimethylsilyloxymethyl)-5-methylisoxazole.

To a chilled (5° C.) solution of 3-hydroxymethyl-5-methylisoxazole (16.8g, 148 mmol) and tert-butyldimethylsilyl chloride (24.6 g, 163 mmol) indry methylene chloride (100 mL) was added over 15 minutes a solution oftriethylamine (22.7 mL, 163 mmol) in methylene chloride (25 mL).4-Dimethylaminopyridine (1.81 g, 14.8 mmol) was added and the thickreaction mixture was stirred at room temperature for 48 hours. Water(100 mL) was added and the aqueous layer extracted with methylenechloride (3×). The combined organic phases were washed with brine, dried(MgSO₄), filtered through a pad composed of a layer of Florisil and alayer of Silica Gel 60, and concentrated in vacuo. The yellow oilobtained (36.6 g) was purified by chromatography (Silica Gel 60, 2%ethyl acetate in hexanes) to give 27.7 g (81.9%) of pure title compoundas a pale yellow oil.

b) 3-[3-(tert-Butyldimethylsilyloxymethyl)isoxazol-5-yl]propyl alcohol.

To a cold (-78° C.) solution of the product from part (a) (13.0 g, 57.0mmol) and N,N,N',N'-tetramethylethylenediamine (1.2 mL, 7.9 mmol) in drytetrahydrofuran (THF) (150 mL) was added over 5 minutes n-butyllithium(31.3 mL, 2.0M in hexane). The bright orange-yellow anion solution wasstirred for 25 minutes. Ethylene oxide (50.0 mL of 7.6M solution in dryTHF) was added over 10 minutes. After 1.5 hours, saturated NH₄ Cl (30mL) was added. The mixture was allowed to warm to room temperature anddiluted with water. The aqueous layer was extracted with ethyl acetate(3×). The combined organic phases were washed with brine, dried (MgSO₄),filtered through a pad of Silica Gel 60, and concentrated in vacuo.Chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) gave 3.44 gof recovered product from part (a) and 8.18 g (52.7%) of pure titlecompound as a colorless oil.

c)3-(tert-Butyldimethylsilyloxymethyl)-5-{3-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-isoxazole.

A solution of the product from part (b) (1.00 g, 3.67 mmol), the productof Example 30b (1.04 g, 4.04 mmol), and triphenylphosphine (1.06 g, 4.04mmol) in dry tetrahydrofuran (THF) (10 mL) was chilled to 0° C. Asolution of diethyl azodicarboxylate (DEAD) (0.61 mL, 1.04 mmol) in dryTHF (15 mL) was added dropwise over 20 minutes. The solution was stirredfor 30 minutes at 0° C. and 18 hours at room temperature, diluted withwater, and extracted with ethyl acetate (2×). The combined organicphases were washed with 10% NaOH, brine, dried (MgSO₄), filtered througha pad of Silica Gel 60, and concentrated in vacuo to give 3.44 g ofyellow oil. Chromatography (Silica Gel 60, 10% ethyl acetate in hexanes)provided 1.73 g (83.6%) of pure title compound as a colorless oil.

d)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-(hydroxymethyl)isoxazole[I; R₁ =CH₂ OH, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅ =hydrogen].

A solution of the product from part (c) (0.75 g, 1.5 mmol),tetrahydrofuran (60 mL), and 1N HCl (7.5 mL) was stirred at roomtemperature for 18 hours and diluted with water (100 mL). The pH wasadjusted to pH 7 (pH paper) with solid NaHCO₃ and extracted with ethylacetate (3×). The combined organic phases were washed with brine, dried(MgSO₄), and concentrated in vacuo to give 0.73 g of yellow oil whichwas purified by chromatography (Silica Gel 60, 50% ethyl acetate inhexanes) to provide 0.58 g (100%) of pure title compound as a whitesolid, mp 92°-3° C. (white needles from ethanol).

EXAMPLE 35

a)3,5-Dimethyl-4-{3-[3-(tert-butyldimethylsilyloxymethyl)-isoxazol-5-yl]propyloxy}benzonitrile.

To a chilled (0° C.) methylene chloride (25 mL) solution of3,5-dimethyl-4-hydroxybenzonitrile (773 mg, 5.26 mmol), the product fromExample 34b (1.43 g, 5.26 mmol), and triphenylphosphine (1.38 g, 5.26mmol) was added dropwise over 30 minutes a solution of diethylazodicarboxylate (DEAD) (915 mg, 5.26 mmol) in methylene chloride (5mL). The solution was stirred at 0° C. for 30 minutes and at roomtemperature for 18 hours, after which it was washed with water, 2.5MNaOH, brine, dried (Na₂ SO₄) and concentrated in vacuo. The residue wastriturated in ether to remove the bulk of the triphenylphosphine oxide,the filtrate concentrated in vacuo, and the residue purified bychromatography (Silica Gel 60, 15% ethyl acetate in hexanes) to give1.73 g (82.2%) of pure title compound as a colorless oil.

b)3,5-Dimethyl-4-{3-[3-(tert-butyldimethylsilyloxymethyl)-isoxazol-5-yl]propyloxy}-N-hydroxybenzenecarboximidamide.

A mixture of the product from part (a) (1.22 g, 3.05 mmol), ethanol (30mL), hydroxylamine hydrochloride (1.06 g, 15.2 mmol), and finely dividedpotassium carbonate (2.10 g, 15.2 mmol) was refluxed for 5 hours andfiltered. The filter cake was washed with ethanol and the combinedfiltrates concentrated in vacuo to give 1.30 g of white solid. A portionof this material (0.78 g) was purified by chromatography (reverse phasesilica gel, 17% water in methanol) to give 0.47 g of title compoundwhich contained approximately 5% (NMR analysis) of desilylated material.

c)5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-(hydroxymethyl)isoxazole[I; R₁ =CH₂ OH, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =cyclopropyl, R₅=hydrogen].

To a solution of the purified product from part (b) (0.47 g, 1.1 mmol)in pyridine (20 mL) was added cyclopropylcarbonyl chloride (0.15 mL, 1.6mmol). The mixture was heated at 90° C. for 26 hours. The pyridine wasremoved in vacuo and the residue partitioned between water and ethylacetate. The aqueous phase was extracted with ethyl acetate (3×). Thecombined organic phases were washed with 3N HCl (2×), brine, dried (Na₂SO₄), and concentrated in vacuo to yield 0.61 g of a yellow oil.Chromatography (Silica Gel 60, 35% ethyl acetate in hexanes) provided0.25 g (62%) of pure title compound as a colorless oil. Cyrstallizationfrom methylene chloride and hexanes provided the title compound as awhite solid, mp 80°-1° C.

EXAMPLE 36

a)5-Cyclopropyl-3-[4-(5-ethoxycarbonyl-4-pentynyloxy)-3,5-dimethylphenyl]-1,2,4-oxadiazole.

To a cold (-78° C.) dry tetrahydrofuran solution (20 mL) of the productfrom Example 24 (1.30 g, 4.41 mmol) was added dropwise n-butyllithium(2.30 mL, 2.3M in hexane) over 15 minutes. After an additional 30minutes at -78° C., ethyl chloroformate (0.63 mL, 6.6 mmol) was addedand the mixture warmed gradually to 0° C. over 2 hours. The reaction wasquenched with saturated NH₄ Cl and extracted with ethyl acetate (3×).The combined organic phases were washed with brine, dried (Na₂ SO₄), andconcentrated in vacuo to give a colorless oil (2.05 g). Chromatography(Silica Gel 60, 10-20% ethyl acetate in hexanes) provided 1.38 g (85.0%)of pure title compound as a colorless oil.

b)5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-hydroxyisoxazole[I; R₁ =OH, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =cyclopropyl, R₅=hydrogen].

A mixture of the product from part (a) (810 mg, 2.20 mmol), ethanol (15mL), hydroxylamine hydrochloride (400 mg, 5.76 mmol), and 10% NaOH (5mL) was stirred at room temperature for 24 hours (after 8 hours, asolution was obtained). Water (6 mL) was added, the mixture acidifiedwith concentrated HCl to pH 2 (pH paper), and extracted with ether (4×).The combined organic phases were washed with brine, dried (Na₂ SO₄), andconcentrated in vacuo to a white solid. Chromatography (Silica Gel 60,50% ethyl acetate in hexanes) provided 0.55 g (70%) of pure titlecompound as a white solid, mp 155°-6° C. (ethyl acetate and hexanes).

EXAMPLE 37

5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]propyl}-3-ethoxyisoxazole[I; R₁ =CH₂ CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =cyclopropyl, R₅=hydrogen].

A mixture of the product of Example 36b (0.30 g, 0.85 mmol), dry acetone(25 mL), finely divided potassium carbonate (0.24 g, 1.7 mmol), andethyl iodide (0.18 mL, 2.2 mmol) was heated at 50° C. for 18 hours,filtered, and concentrated in vacuo to give a pinkish solid.Chromatography (Silica Gel, 50% ethyl acetate in hexanes) provided 0.19g of slightly impure title compound and 0.12 g (37%) of a pure sideproduct (the corresponding 2,3-dihydro-2-ethyl-3-oxoisoxazole compound)as a colorless oil. Pure title compound was obtained by chromatography(reverse silica gel, 20% water in methanol); yield 0.14 g (43%), mp70°-1° C. (methanol).

EXAMPLE 38

5-{3-[4-(5-Aminocarbonyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]propyl)-3-methylisoxazole[I; R₁ =CH₃, Y=CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CONH₂, R₅ =hydrogen].

Finely divided product of Example 7 (3.08 g, 8.00 mmol) was added to 10%ethanolic ammonia (80 mL). After 15 minutes, a solution was obtained anda fine precipitate started to form. After 4 hours, the mixture wasfiltered and the solids obtained washed with cold ethanol to give 2.35 g(82.5%) of pure title compound as a fine white powder, mp 177°-8° C.(iso-propyl acetate).

EXAMPLE 39

5-{3-[4-(5-Cyano-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CN, R₅ =hydrogen].

To a chilled (0° C.) suspension of the product of Example 38 (1.60 g,4.50 mmol) and dry pyridine (11.2 mL) in dry tetrahydrofuran (27 mL) wasadded trifluoroacetic anhydride (1.90 mL, 13.5 mmol). The mixture wasstirred at 0° C. for 4 hours and at room temperature for 18 hours,diluted with water (100 mL), and extracted with ethyl acetate (2×25 mL).The combined organic phases were washed with 1N HCl (3×), brine, dried(MgSO₄), and concentrated in vacuo. The red solid obtained (1.67 g) waschromatographed (Silica Gel 60, 20% ethyl acetate in hexanes) to give1.38 g (90.8%) of pure title compound as a white solid, mp 93°-4° C.(ethyl acetate and hexanes).

EXAMPLE 40

5-{3-[2,6-Dimethyl-4-(5-(hydroxymethyl)-1,3,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CH₂ OH, R₅ =hydrogen].

A mixture of the product of Example 9 (4.12 g, 10.7 mmol) and finelydivided potassium carbonate (1.48 g, 10.7 mmol) in dry methanol (40 mL)was stirred at room temperature for 15 minutes and partitioned betweenwater (50 mL) and ethyl acetate (50 mL). The aqueous phase was extractedwith ethyl acetate (1×25 mL) and the combined organic phases washed withbrine, dried (MgSO₄), and concentrated in vacuo. Chromatography (SilicaGel 60, 50% ethyl acetate in hexanes) provided 3.35 g (91.2%) of puretitle compound as a white solid, mp 116.5°-117° C. (ether).

EXAMPLE 41

5-{3-[2,6-Dimethyl-4-(5-(iodomethyl)-1,2,4-oxadiazol-3-yl)-phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CH₂ I, R₅ =hydrogen].

A solution of sodium iodide (0.45 g, 3.0 mmol) in dry acetone (5 mL) wasadded dropwise to a solution of the product of Example 10 (905 mg, 2.50mmol) in dry acetone (5 mL). After 4 hours, the yellow suspension waspoured into water (50 mL) and extracted with methylene chloride (3×25mL). The combined organic phases were washed with brine, dried (MgSO₄),and concentrated in vacuo to give a brown oil (1.56 g). Filtrationthrough Florisil (methylene chloride) provided a green-yellow oil (1.43g) which solidified upon standing at 0° C. Chromatography (Silica Gel60, 25% ethyl acetate in hexanes) provided 1.06 g (93.8%) of pure titlecompound as a pale yellow solid, mp 89°-90° C. (white needles fromether-pentane).

EXAMPLE 42

5-{3-[2,6-Dimethyl-4-(5-(4-methylphenylsulfonyloxymethyl)-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃ R₂ and R₃ =2,6-(CH₃)₂, R₄ =4-CH₃ C₆ H₄ SO₂ OCH₂,R₅ =hydrogen).

To a chilled (0° C.) mixture of the product of Example 40 (343 mg, 1.00mmol) and finely divided potassium carbonate (0.28 g, 2.0 mmol) in drymethylene chloride (5 mL) was added dropwise a filtered solution ofp-toluenesulfonyl chloride (0.23 g, 1.2 mmol) in methylene chloride (2mL). The mixture was stirred at room temperature for 72 hours, afterwhich an additional 0.40 mmol of potassium carbonate andp-toluenesulfonyl chloride was added. After 24 hours, the mixture waspartitioned between water (10 mL) and ethyl acetate (10 mL). The organicphase was washed with 1N NaOH (1×5 mL), brine, dried (MgSO₄), andconcentrated in vacuo. Chromatography (Silica Gel 60, 40% ethyl acetatein hexanes) provided 478 mg (96.1%) of pure title compound as a whitesolid, mp 97°-8° C. (ether).

EXAMPLE 43

5-(3-[2,6-Dimethyl-4-(5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CH₂ CF₃, s R₅=hydrogen].

A mixture of the product of Example 1d (4.55 g, 15.0 mmol), drytetrahydrofuran (45 mL), 2-trifluoro-ethylidene-1,3-dithiane (3.60 g,18.0 mmol), and silver trifluoroacetate (7.3 g, 33 mmol) was refluxed inthe dark for 22 hours, cooled to room temperature, and filtered. Thegreen filter cake was washed with ethyl acetate (4×20 mL). The combinedfiltrates were concentrated in vacuo. The residue obtained was dissolvedin methylene chloride (50 mL) and washed with water (3×25 mL), 0.1MNaHCO₃ (freshly prepared, 25 mL), brine, dried (MgSO₄), filtered througha pad of Florisil, and concentrated in vacuo to give 5.39 g of a yellowpaste. Purification by chromatography (Silica Gel 60, 15% ethyl acetatein hexanes) provided 2.22 g (37.5%) of pure title compound as a whitesolid, mp 84°-85° C. (methanol) (white plates).

EXAMPLE 44

5-{3-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-(2-hydroxyethoxy)isoxazole[I; R₁ =HOCH₂ CH₂ O, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =cyclopropyl,R₅ =hydrogen).

A mixture of the product of Example 36b (0.75 g, 2.1 mmol), dry acetone(25 mL), finely divided potassium carbonate (0.32 g, 2.3 mmol), and2-bromoethanol (0.19 mL, 2.7 mmol) was refluxed for 5 hours, filtered,and concentrated in vacuo to give a pinkish oil. Chromatography (SilicaGel 60, 50% ethyl acetate in hexanes) provided 0.51 g of impure titlecompound and 0.48 g (57%) of a pure side product (the corresponding2,3-dihydro-2-(2-hydroxyethyl)-3-oxo-isoxazole compound) as a whitesolid. Pure title compound (0.31 g, 37%) was obtained by gradiantchromatography (Silica Gel 60, hexanes to 50% ethyl acetate in hexanes),mp 64°-65° C. (methylene chloride and hexanes).

Following a procedure similar to that of Example 1c but substituting for3,5-dimethyl-4-hydroxybenzonitrile an equivalent amount of thefollowing:

4-hydroxy-3-nitrobenzonitrile

4-hydroxy-3,5-dimethoxybenzonitrile

4-hydroxy-3-trifluoromethylbenzonitrile

there can be obtained respectively the following compounds of formulaIX:

4-[3-(3-methylisoxazol-5-yl)propyloxy]-3-nitrobenzonitrile

3,5-dimethoxy-4-[3-(3-methylisoxazol-5-yl)propyloxy]-benzonitrile

4-[3-(3-methylisoxazol-5-yl)propyloxy]-3-(trifluoro-methyl)benzonitrile.

EXAMPLE 45

a) Methyl (3,5-dimethyl-4-hydroxy)benzoate.

A mixture of 9.97 g (60 mmol) of 3,5-dimethyl-4-hydroxybenzoic acid, 20ml of methanol, 100 ml of dichloroethane, and 2 ml of conc. sulfuricacid was refluxed for 20 h. The reaction mixture was cooled to roomtemperature, washed with water (2×25 ml), saturated sodium bicarbonatesolution (2×25 ml), and brine, and dried over magnesium sulfate. Theorganic layer was filtered through a short plug of florisil withmethylene chloride and the filtrate was concentrated in vacuo to afford10.2 g (94.4%) of the title ester, m.p. 124°-128° C.

b) N-Hydroxy-cyclopropylcarboximidamide.

Sodium metal 575 mg (25 mmol ) was dissolved in 15 ml of dry methanol(dried over 4 A Molecular sieves) and the resulting solution was addeddropwise to a suspension of 1.74 g (25 mmol) of hydroxylaminehydrochlorlde in 5 ml of dry methanol. The mixture was stirred for 1 hand filtered. To the above filtrate was added 1.84 g (25 mmol) ofcyclopropylcyanide and the reaction mixture was refluxed overnight.After cooling, the mixture was filtered and the filtrate wasconcentrated in vacuo yielding 2.32 g of a thick oil. The thick oil wasdissolved in 2ml of methanol, filtered, and concentrated in vacuoaffording 1.74 g (69.6%) of the title compound as a colorless thick oil.

c) 3-(3-Methylisoxazol-5-yl)propyl alcohol.

3,5-Dimethylisoxazole (220g, 2.27 mol) in 2.2 L of tetrahydrofuran undernitrogen was cooled with stirring to -75° C. and 908 ml of 2.5Mn-butyllithium 92.27 mol) in hexane were added over 1 h, keeping thetemperature at or less than -65° C. The chilled solution was stirred forthirty minutes after addition was complete and was then treated at about-70° C. with a solution of 112 g (2.54 mol) of ethylene oxide in 390 mltetrahydrofuran over a period of 1.5 h, keeping the temperature at about-65° C. and stirred overnight. The mixture was quenched at 8° C. byadding 1.2 L of 2.5M hydrochloric acid over a period of 20 min, duringwhich time the temperature rose to 23° C., and was stirred for 10 min.The organic phase was separated, washed with 500 ml of water, andconcentrated to give 147 g (46%) of title compound as a brown oil. Thecombined aqueous phases (original+water wash) were extracted with methyltert-butyl ether (3×200 ml) and the combined organic extracts wereconcentrated to give an additional 125 g (39%) of title compound as abrown oil.

d) 3-(3-Methylisoxazol-5yl)propyl chloride.

To the product from part (a) (125 g, 0.885 mol) in 1225 ml methylenechloride was added 192 ml (2.62 mol) of thionyl chloride over a periodof 1 h during which time the temperature rose to 40° C. to a gentlereflux. Heating at reflux was continued for 3 h, the reaction mixturewas allowed to stand overnight, and then heating at reflux was continuedfor 1 h. The reaction mixture was added as a steady stream to 3 kg ofice water with vigorous stirring, and stirring was continued for 1 h andthe aqueous phase was separated. Water (1 L) was added to the organicphase followed by 161 g of solid sodium bicarbonate in portions withvigorous stirring. The organic phase was separated and concentrated invacuo to give a black oil which was purified by wiped-film distillationto give 94 g of the title compound as a yellow oil, b.p. 65° C./0.09 mm.

e) Methyl 3,5-dimethyl-4-[3-(3-methylisoxazol 5yl]propyloxy]benzoate.

A mixture of 10.1 g (56 mmol) of methyl 3,5-dimethyl-4-hydroxybenzoate,100 ml of dry N-methyl-2-pyrrolidinone, 15.5 g (112 mmol) of milledpotassium carbonate, 0.93 g (5.6 mmol) of potassium iodide, and 11.2 ml(84 mmol) of the product from part (d) was stirred at 65° C. for 18 h.To the above mixture additional chloride from part (d) (1.9 ml) andmilled potassium carbonate (1.9 g) were added and the resulting mixturewas stirred at 65° C. for 6 h. The mixture was poured into 200 ml ofwater and the aqueous layer was extracted with ether (3×50 ml). Thecombined organic layer was washed with water (2×25ml), brine, dried overmagnesium sulfate, and concentrated in vacuo to provide 22.2 g of acrude product. MPLC (Silica Gel 60 50×460 mm, 25% ethyl acetate inhexane, 60 ml/min) provided 16.6 g (92.6%) of pure title compound.

f) 3.5-Dimethyl-4-[3-(3-methylisoxazo15yl)propyloxy] benzoic acid.

A mixture of the product prepared according to part (e) (7.58 g, 25mmol), 80 ml ethanol/water (1:1), and 1.2 g (30 mmol) of sodiumhydroxide was refluxed for 1 h. The mixture was cooled to roomtemperature, ethanol was removed in vacuo, and the aqueous layer waswashed with 20 ml of ether. To the above aqueous layer was added 1.72 ml(30 mmol) of glacial acetic acid, the resulting mixture was chilled andfiltered. The residue was washed with water and dried in vacuo (65°C./0.1 mm, 18 h with P₂ O₅) to provide 6.9 g (95.4%) of the titlecompound as a white solid, m.p. 160°-162° C.

g) 3.5-Dimethyl-4[3-(3-methylisoxazol5yl)propyloxl benzoyl chloride.

To 2.8 g (10 mmol) of3,5-dimethyl-4[3-(3-methylisoxazol-3-yl)propyloxy]-benzoic acid (theproduct prepared according to part (e)) was added 1.72 ml (20 mmol) ofoxalyl chloride and the mixture was stirred at room temperature for 1 hand then refluxed for 2 h. The mixture was concentrated in vacuoaffording 3.1 g of the title compound as a dark red oil.

h) 1.2895 g. 4-cyano, 2-6-dimethylphenol (8.76 mmols), was taken up in25 mls. of absolute ethanol to which was added 3.04 g. (43.8 mmol) ofhydroxylamine hydrochloride (H₂ NOH.HCl) followed by potassium carbonate(6.05 g) and stirred for 72 hours. Reaction mixture was filtered, rinsedwith ethanol, and concentrated under vacuum giving 1.77 g. of an offwhite material as the amideimide product.

i) 1.77 g. of the amideimide product from above (8.8 mmol) was taken upin 10 mls. of pyridine. To this mixture was added 3.7 g. (35 mmols)cyclopropyl carbonylchloride via syringe, dropwise. Upon addition aprecipitate formed, the reaction mixture was diluted with ether andpoured into a separatory funnel. The ether layer was extracted with 1mmol of HCl, water and aqueous potassium bicarbonate. Dried over sodiumsulfate filtered and concentrated in vacuo to give a solid which wascrystalized in ether. The m.p. 134° C. to 135° C.

j) Product from above (0.56 g.) was suspended in toluene and heated toreflux for 36 hours until the solution became clear. The reactionmixture was concentrated in vacuo a quantitative yield of1,2,4-oxadiazole product. 162.5 mg (0.51 mmols) of this product wassuspended in sodium methoxide (26.8 mg, 0.05 mmol/methanol) and stirredat room temperature for three days. The product was then diluted withwater and neutralized with 1M of HCl and extracted with ether. Etherfractions were combined and were washed with aqueous 1.5M potassiumcarbonate and then dried over magnesium sulfate filtered andconcentrated in vacuo in 82.6 mg of the phenol. m.p. 94.5° C. to 95.5°C.

k)5-{3-[2,6-Dimethyl-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole.[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =cyclo-propyl, R₅=hydrogen].

To a solution of the product from part (b) (1.05 g, 10.5 mmol) in 10 mlof dry pyridine heated to 45° C. was added dropwise a solution of theproduct from part (g) (3.1 g, 10 mmol) in 10 ml of dry THF and themixture was heated to reflux for 1 h and concentrated in vacuo. Theresidue was partitioned between 50 ml of ethyl acetate and 25 ml ofwater, the organic layer was washed with water (2×25 mi), brine, anddried over magnesium sulfate. The organic layer was concentrated invacuo to provide 3.4 g of a product which was heated at 145° C. in vacuofor 10 min and cooled. MPLC (Silica Gel 60 26×460 mm, 15% ethyl acetatein hexane, 20 ml/min) provided 1.48 g (41.9%) of pure title compound.The product was recrystallized from methanol and dried in vacuo toafford 1.28 g of the title compound.

EXAMPLE 46

a) N-hydroxy-trifluoroacetoximidamide.

Sodium metal (575 mg, 25.0 mg-atom) was dissolved in 15 ml of drymethanol (dried over 4 A Molecular sieves) and the resulting solutionwas added dropwise to a suspension of 1.74 g (25 mmol) of hydroxylaminehydrochloride in 5 ml of dry methanol. The mixture was stirred at roomtemperature for 1.5 h and filtered. The above filtrate was cooled to 0°C., 2.7 g (28 mmol) of trifluoroacetonitrile was slowly bubbled in andthe resulting mixture was stirred at room temperature for 18 h. Themixture was filtered, concentrated in vacuo, and the residue (thin oilwith white solid) was dissolved in chloroform and filtered throughsuper-cel. The filtrate was concentrated in vacuo to provide 2.84 g(89.4%) of the title compound.

b)Methylamidino-3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl)propyl]oxy]benzoate.

A solution of 3.08 g (10 mmol)3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl)propyl]oxy]benzoyl chloride(the product prepared according to part (1 g)) in 10 ml of dry THF wasadded dropwise to a solution of 1.41 g (11 mmol) of the product frompart (2a) in 10 ml of dry pyridine (over 4A sieves) and the mixture wasstirred at room temperature for 1 h. An additionalN-hydroxy-trifluoroacetoximidamide (0.2 g, 2a) was added and the mixturewas stirred at room temperature for 1 h. The reaction mixture wasconcentrated in vacuo, the residue partitioned between 25 ml of waterand 25 ml of ethyl acetate, and the aqueous layer was extracted withethyl acetate (2×15 ml). The combined organic layer was washed withwater (3×15 ml), brine, and the organic layer was dried over magnesiumsulfate and concentrated in vacuo. The residue (partial solid) wasdissolved in 10 ml of ethyl acetate and concentrated (this procedurerepeated 2×) to provide 4.31 g of the title compound.

c) A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =trifluoromethyl. The product from part 46b, 4.31g washeated at 145° C. for 1 h and at 155° C. for 4.5 h. A dark solidproduct, after cooling, was purified by flash chromatography (silica gel60, 2.8×35 cm) eluting with methylene chloride to afford 1.28 g (33.6%)of the title compound which was recrystallized from methanol. MPLC(Silica Gel 60 26×460 mm, 5% ethyl acetate in methylene chloride, 20ml/min) provided 931 mg (18.9%) of pure title compound. The product wasrecrystallized from ethyl acetate and dried in vacuo to afford 527 mg ofthe title compound, m.p. 175°-176.5° C.

EXAMPLE 47

A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =amino. To a suspension of 30 g of powdered 4A sievesin 180 ml of absolute ethanol was added 4.14 g (180 mg-atom) of sodiummetal. After all Na dissolved, 12 g of hydroxyguanidine sulfate hydratewas added and the mixture was stirred for 1 h at room temperature. Tothe above mixture a solution of 4.55 g (15 mmol) of methyl3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl) propyl]oxy]-benzoate (theproduct prepared according to (1e)) in 5 ml of absolute ethanol wasadded and the resulting mixture was refluxed for 2 h, concentrated invacuo, and the residue was partitioned between 100 ml of water and 50 mlof ethyl acetate. The aqueous layer was extracted with ethyl acetate(2×25ml), the combined organic layer was washed with brine, dried overmagnesium sulfate, and concentrated in vacuo to provide 1.65 g of ayellow solid.

EXAMPLE 48

a) A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =2-furyl.

Hydroxy3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl)propyl]oxy]-benzenecarboximidamide(1.52 g, 5 mmol) was dissolved in 30 ml of acetone and 0.83 g (6 mmol)of potassium carbonate was added to the solution. The mixture wasstirred and cooled to 0° C., 0.6 ml (6 mmol) of furoyl chloride wasadded dropwise via syringe over 2 min, and the resulting reactionmixture was stirred 15 min in ice bath and stirring of a solid mixturecontinued for 2.5 h at room temperature. The resulting mixture wasfiltered, the residue washed with acetone, and the combined filtrateswere concentrated in vacuo to provide 1.939 g of a nearly white solid.The solid product was heated (mp 130° C.) neat in an oil bath undernitrogen, and the liquid product was heated at 150° C. for 20 min andcooled to provide 1.8 g of a brown cake. The solid which dissolved in 35ml of methylene chloride was purified by passing through a wet-packedsilica gel column (196 g; 40×330 mm) with methylene chloride/ethylacetate (96:4) to provide 1.278 g (67%) of the title compound, as awhite solid, m.p. 123.5°-125° C.

b) A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =2-thienyl. Hydroxy3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl)propyl]oxy]benzenecarboximidamide(0.5 g, 1.65 mmol) was suspended with stirring in 10 ml of acetone and0.25 g (1.81 mmol) of potassium carbonate. The mixture was stirred andcooled to 0° C., 0.2 ml (1.81 mmol) of 2-thiophenecarbonyl chloride wasadded dropwise in 30 sec, and the resulting reaction mixture was stirred20 min in ice bath and the stirring continued for 20 min at 0° C. Thereaction mixture was filtered, the filtrate was concentrated in vacuo toprovide 804 mg of viscous colorless liquid. The liquid was heated neatin an oil bath under nitrogen at 125° C. for 15 min and cooled toprovide 727 mg of a solid cake. The solid was dissolved in 20 ml ofmethylene chloride/ethyl acetate (95:5) and purified by passing througha wet-packed silica gel 60 (41 g; 22×255 mm) with methylenechloride/ethyl acetate (95:5) to provide 363 mg (56%) of the titlecompound, as a white solid. The product was recrystallized from ethylacetate and dried at 60° C. in vacuo to provide 207 mg (32%) of a whitesolid, m.p. 115°-116° C.

c) A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =1-acetoxyethyl.

Hydroxy3,5-dimethyl-4-[[3-(3-methyl-5-isoxazolyl)propyl]oxy]benzenecarboximidamide(4.45 g, 15 mmol) was suspended at 0° C. with stirring in 45 ml of dryacetone and 2.28 g (16.5 mmol) of potassium carbonate. The mixture wasstirred and cooled to 0° C., a solution of 2.48 g (16.5 mmol) of2-acetoxypropionyl chloride in 8 ml of dry acetone was added dropwise,and the resulting reaction mixture was stirred 15 min at 0° C. Themixture was poured into 100 ml of water and the aqueous layer wasextracted with methylene chloride (3×25 ml). The combined organic layerwas washed with brine, dried over magnesium sulfate, and concentrated invacuo to provide 8.05 g of a light yellow solid which was heated neat at120° C. for 15 min and cooled. The product was dissolved in methylenechloride, dried over magnesium sulfate, filtered through Florisil withmethylene chloride, and concentrated in vacuo to provide 7.52 g of ayellow oil. Repeated MPLC (Silica Gel 60 50×460 mm, 3% ethyl acetate inhexane) provided 1.06 g of pure title compound, m.p. 77°-77.5° C.

d) A compound of formula I wherein R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =1-hydroxyethyl. 3.6 g, 9 mmol of the product preparedin 48c was dissolved in 36 ml of dry methanol. To the above solution wasadded 1.24 g (9 mmol) of milled potassium carbonate and the mixture wasstirred at room temperature for 0.5 h. The mixture was partitionedbetween 25 ml of water and 50 ml of methylene chloride. The aqueouslayer was extracted with methylene chloride (2×25 ml), the combinedorganic layers washed with brine, dried over magnesium sulfate, andconcentrated to provide 3.65 g of a pale yellow oil. MPLC (Silica Gel 6026×460 mm, 40% ethyl acetate in hexane) provided 3.15 g (97.8%) of puretitle compound as a white solid which was recrystallized from ethylacetate, m.p. 83°-87° C.

EXAMPLE 49

a) 1.0 g. (1.5 mmol) of 4-bromo-6-chloro-o-cresol, 0.6 g. (6.7 mmol) ofCuCN was combined in 5 mls DMF and heated to reflux, forming an ambersolution. Solution was refluxed for 5 hours and was cooled and pouredinto a separatory funnel with aqueous 2N HCl and ethyl acetate and wasextracted three times with ethyl acetate. Combined organic layers weredried over magnesium sulfate, filtered, and concentrated in vacuo to abrown oil. The brown oil was taken up in a minimal amount of methylenechloride and put through a column of silica gel and eluted with 10%ethyl acetate/hexane. Appropriate fractions were concentrated in vacuoto give (210 mg) 28% of a white solid m.p.101° C.

b) 100 mgs. of the compound of Example 49 and 143 mgs. of3-methyl-5-(3-chloropropyl)-isoxazole, 207 mg. of K₂ CO₃, 100 mgs. of KIwas combined in 2 mls of NMP and heated to 60° C. for 72 hours. Thereaction mixture was cooled, and water and ethyl acetate were added, thelayers were separated and extracted three times with ethyl acetate.Combined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo to a yellow oil. The oil was taken up in a minimalamount of methylene chloride and applied to a silica column which waseluted with 10% ethyl acetate/hexane and the appropriate fractions wereconcentrated in vacuo giving 126 mg (72%) of a white solid m.p. 41.0 °C. to 42.0° C.

c) 4.20 g. (14 mmol) of the compound of Example 49b 13.80 g. (26 mmol)of hydroxylamine HCl, 9.66 g. (70 mmol) of potassium carbonate K₂ CO₃were combined in 100 ml of ethanol and heated to reflux for 9 hours andthen cooled. Reaction mixture was hot filtered with ethanol andconcentrated in vacuo to a solid. The solid was taken up in a minimalamount of methylene chloride, filtered and then concentrated in vacuo toa white solid which was triturated in ether, filtered and dried to asolid under high vacuum giving 4.06 g. (90%) of the amidoxime.

d)5-{3-[2,-Methyl-6-chloro-4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ =CH₃, R₃ =Cl, R₄ =difluoromethyl, R₅ =hydrogen].

A mixture of3-methyl-5-chloro-4-[3-(3-methylisoxazol-5-yl)propyloxy]-N-hydroxybenzenecarboximidamide(400 mg, 1.2 mmol) and 2 ml of ethyl difluoroacetate was heated at 100°C. under nitrogen for 7 h and cooled. The mixture was concentrated invacuo, the white solid residue was dissolved in methylene chloride andpurified by silica gel chromatography eluting with 10% ethylacetate/hexane to provide a white solid which was recrystallized fromether/hexane, yielding 142 mg (31%) of the title compound, m.p. 75°-76°C.

e)5-{3-[2,6-Dimethyl-4-(5-difluorobromomethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =difluorobromomethyl, R₅=hydrogen].

A mixture of3,5-dimethyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxybenzenecarboximidamide(758 mg, 2.5 mmol) and 0.96 ml (7.5 mmol) of ethyl difluorobromoacetatewas heated at 105° C. for 18 h and cooled. The mixture was partitionedbetween 20 ml of ethyl acetate and 10 ml of water, the organic layer waswashed with 1 N HCl, brine, dried over magnesium sulfate, andconcentrated to provide 1.12 g of a red oil. The red oil was filteredthrough Florisil with methylene chloride to yield 400 mg of the product.MPLC (Silica Gel 60 26×460 mm, 15% ethyl acetate in hexane, 20 ml/min)and recrystallization from methanol and drying provided 292 mg of puretitle compound as a white solid, m.p. 76°-77° C.

f) Ethyl 2,2-difluoropropionate

Diethylaminosulfur trifluoride (3.63 ml, 27.5 mmol) was added dropwiseto 2.9 g (25 mmol) of freshly distilled ethyl pyruvate at 0° C., and themixture was slowly warmed to room temperature and stirred overnight. Thereaction mixture was chilled in an ice bath, 2.5 ml of water was addeddropwise, and stirred for 15 min. The mixture was partitioned between 25ml of water and 15 ml of ether, the organic layer was washed with water,brine, and dried over magnesium sulfate. The organic solution wasconcentrated in vacuo to provide 2.1 g (60.9%) of the title compound asa yellow oil.

g)5-{3-[2,6-Dimethyl-4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =difluoromethyl, R₅=hydrogen].

A mixture of3,5-dimethyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxybenzenecarboximidamide(1.52 g, 5 mmol) and 2.07 ml (15 mmol) of ethyl difluoropropionate, and0.5 ml of dry N-methylpyrrolidinone was heated at 105° C. for 22 h andcooled. The mixture was diluted with 25 ml of water, extracted withethyl acetate (2×25 ml), and the organic layer was washed with water(2×25ml), brine, and dried over magnesium sulfate. The organic layer wasconcentrated in vacuo to provide 1.62 g of a brown oil. MPLC (Silica Gel60 26×460 mm, 15% ethyl acetate in hexane, 20 ml/min) andrecrystallization from methanol and drying provided 618 mg of pure titlecompound as a white solid, m.p. 64°-65° C.

EXAMPLE 50

a) 5-(t-Butyldiphenylsilyloxy)-1-pentyne. Imidazole (9.29 g (136 mmol)was dissolved in 50 ml of DMF under nitrogen with stirring. To thissolution was added 18.75 g (17.74 mmol) of t-butyldiphenylsilyl chlorideand 5.27 g (5.55 mmol) of 4-pentyn-1-ol and the mixture was stirred atroom temperature for 2 h. The mixture was carefully diluted with 300 mlof water, extracted with ethyl acetate, and the organic layer was washedwith water, brine, and dried over magnesium sulfate. The organicsolution was concentrated in vacuo to provide 22.66 g of a yellow oilwhich was purified by passing through 150 g pad of silica gel elutingwith hexane and 3% ethyl acetate in hexane affording 17.56 g (86.8%) ofthe title compound as a clear oil.

b)3-(ethoxycarbonyl)-5-[3-(t-butyldiphenylsilyloxy)propyl] isoxa-zole.

Ethyl chlorooximidoacetate (16.96 g, 0.112 mol) was dissolved in 50 mlof DMF with stirring under nitrogen and 12.03 g (37.3 mmol) of5-(t-butyldiphenylsilyloxy)-1-pentyne in 20 ml of DMF was added over a15 min period. The mixture was stirred at room temperature for 45 min,heated to between 80°-90° C., and 15.6 ml of triethylamine in 30 ml ofDMF was added dropwise over a period of 2.25 h. The heating wascontinued for an additional hour and the mixture was cooled, dilutedwith 20 ml of water, and extracted with ethyl acetate(3×). The combinedorganic layer was washed with water, 10% KHSO₄ solution (2×), water,brine, and dried over magnesium sulfate. The organic solution wasfiltered through a pad of silica and the filtrate concentrated in vacuoto provide 21.97 g of a red-brown oil which was purified by passingthrough 150g of silica gel column, eluting with 2% ethyl acetate inhexane affording 17.9 g (86.8%) of a pale yellow oil. MPLC (Silica Gel60 26×460 mm, 10% ethyl acetate in hexane, 20 ml/min) provided 12.5 g(76.6%) of pure title compound as a clear oil.

c) 3-(Hydroxymethyl)-5-[3-(t-butyldiphenylsilyloxy)-propyl]isoxazole.

A solution of3-(ethoxycarbonyl)-5-[3-(t-butyldiphenylsilyloxy)propyl]isoxazole (4.13g, 9.44 mmol) in 25 ml of THF was added dropwise to a stirred suspensionof 0.72 g (18.87 mmol) of LAH in 20 ml of THF at a rate to cause gentlereflux. The mixture was stirred at room temperature for 5 min. Thereaction mixture was chilled (0° C.) and treated dropwise sequenciallywith water (0.72 ml), 0.72 ml of 15% NaOH solution, and then 2.6 ml ofwater. The mixture was stirred until it became milky and white, andpotasium carbonate and magnesium sulfate were added. The mixture wasfiltered, the filtrate was concentrated in vacuo to provide 3.57 g of apale yellow oil. This oil was chromatographed twice by passing through(silica gel, 50% ethyl acetate in hexane to provide 3.11 g (83.4%) ofthe title compound as a clear colorless oil.

d) 3-(Ethylthiomethyl)-5-[3-t-butyldiphenylsilyloxy)-propyl]isoxazole.

A mixture of3-(hydroxymethyl)-5-[3-(t-butyldiphenylsilyloxy)propyl]isoxazole (5.5 g,13.9 mmol) and triethylphosphine (8.21 g, 69.5 mmol) in 55 ml of THF wasstirred under nitrogen and ethyl disulfide (8.48 g ) was slowly addedand the resulting mixture was stirred at room temperature for 0.5 h,refluxed for 1 h, and stirred at room temperature overnight. The mixturewas concentrated in vacuo, the residue was diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, and dried over magnesium sulfate. The organicsolution was concentrated in vacuo to provide 11.11 g of a yellow oilwhich was purified by two silica gel chromatography separations elutingwith 5-20% ethyl acetate in hexane to afford 3.14 g of the titlecompound as a clear oil.

e) 3-(Ethylthiomethyl)-5-[3-(hydroxy)propyl]isoxazole.

A mixture of3-(ethylthiomethyl)-5-[3-(t-butyldiphenylsilyloxy)propyl]isoxazole (6.55g, 14.9 mmol) and 29.81 ml (29.81 mmol) of 1M TBAF in hexane and 300 mlof THF was allowed to stir under nitrogen overnight. An additional 1 eqTBAF (14.9 ml) was added to the mixture and stirring at room temperaturewas continued for 2 h. The reaction mixture was concentrated in vacuo,the residue was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate,concentrated in vacuo to provide a pale yellow oil which was purified bysilica gel (6.6×11 cm) chromatography eluting with 75% ethyl acetate inhexane to provide 2.82 g (94%) of the title compound as a clear oil.

f)5-(3-[2,6-Dimethyl-4-f5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl)-3-(ethylthiomethyl)isoxazole.[R₁ =C₂ H₅ SCH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =trifluoromethyl,R₅ =hydrogen]. 3-(Ethylthiomethyl)-5-[3-(hydroxy)propyl]isoxazole (1.14g, 5.66 mmol), 1.61 g (6.23 mmol) of2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenol, and 1.63g of triphenylphosphine were combined in 15 ml of THF under nitrogenwith stirring. The mixture was chilled to 0° C. and 0.89 ml of diethylazodicarboxylate (DEAD) in 5 ml of THF was added dropwise over a 10 minperiod. The resulting orange-red reaction mixture was allowed to warm toroom temperature and stirred for 48 h. The mixture was diluted withwater, extracted with ethyl acetate, and the organic layer was washedwith 5% NaOH solution, water, brine, and dried over magnesium sulfate.The organic solution was passed through a Florisil pad and silica gel(2.4×1.5 cm), concentrated in vacuo to provide 4.92 g of a pale yellowsolid. The solid product was passed through silica gel (2.5×12 cm)eluting with 20% ethyl acetate in hexane to provide 2.34 g of an oil.MPLC (120 g Silica Gel 60, 5% ethyl acetate in hexane, 20 ml/min)provided 2.15 g (86%) of pure title compound as a clear oil.Recrystallization from methanol afforded 1.88 g of a white solid, m.p.36.5°-380° C.

g)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(ethylsulfinomethyl)isoxazole.[R₁ =C₂ H₅ S(O)CH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen].

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(ethylthiomethyl)isoxazole(1.0

g), 1.39 g of Al₂ O₃, 2.27 g of oxone, and 12 ml of dry methylenechloride were combined under nitrogen at room temperature and stirredfor 0.5 h. The mixture was heated to gentle reflux for 5 h and cooled toroom temperature. Magnesium sulfate was added to the mixture, theresulting reaction mixture was filtered and the filtrate concentrated invacuo. The residue was treated with cold methanol (-78° C.) to provide650 mg of the title compound as a white solid.

h)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(ethylsulfonylmethyl)isoxazole.[R₁ =C₂ H₅ S(O₂)CH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen].

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(ethylthiomethyl)isoxazole(0.88 g, 1.99 mmol), 1.99 g of Al₂ O₃, 3.68 g of oxone, and chloroformwere combined under nitrogen at room temperature and stirred for 3 h.The mixture was heated to gentle reflux for 20 h, cooled to roomtemperature, and dried over magnesium sulfate. The mixture was filteredand the filtrate concentrated in vacuo to provide 1.09 g of a paleyellow solid. The solid was passed through silica gel column (2.0×11 cm)eluting with 50% ethyl acetate in hexane to provide 870 mg (92.6%) ofthe title compound. The product was crystallized by dissolving in aminimum volume of methylene chloride and then diluting withether/hexane; m.p. 94°-95° C.

EXAMPLE 51

a) 38.56 g. (0.555 mol.) of NH₂ OH.HCl and 76.69 g. of K₂ CO₃ in 400 ml.of ethanol with vigorous stirring and was combined with 16.33 g. (0.111mol.) of 2-6-dimethyl-4-cyan6phenol. The mixture was heated to refluxfor 43 hours and cooled in an ice bath. Precipitate formed and wasfiltered off, precipitate was then washed with methanol (300 ml.),filtrate was concentrated in vacuo giving 30.67 g. of a tan solid whichwas used unpurified in the next step. 0.111 mol. of the amidoxime fromPart A was dissolved in 60 mls. of pyridine, 78.36 mls. (0.555 mol.) oftrifluoroacedicanhydride was added dropwise over one hour. Reactionmixture was diluted with approximately 1 liter of ice cold water and tansolids filtered off via suction filtration. The filtrate was dried withMgSO₄, filtered through silica gel and concentrated in vacuo yielding18.84 rams of a brown oil. This brown oil was placed on a silica gelcolumn and diluted with 20% EtOAc/hexane and the appropriate fractionswere combined, dried over MgSO₄ filtered and concentrated in vacuoyielding 7.34 g. of the desired oxadiazolylphenol.

b)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methylthiomethyl)isoxazole.[R₁ =CH₃ SCH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =trifluoromethyl,R₅ =hydrogen]. This compound was prepared by a procedure similar to thatof Example 6f employing3-(methylthiomethyl)-5-[3-(hydroxy)-propyl]isoxazole,2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenol,triphenylphosphine, and DEAD.

c)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methylsulfinomethyl)isoxazole.[R₁ =CH₃ S(O)CH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen].

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methylthiomethyl)isoxazole(1.87 g, 4.37 mmol), 4.37 g of Al₂ O₃, 2.69 g of oxone, and 22 ml of drymethylene chloride were combined under nitrogen at room temperature andthe mixture was heated to gentle reflux for 2 h and stirred at roomtemperature overnight. The resulting reaction mixture was filtered andthe filtrate concentrated in vacuo to provide 2.35 g of a white solid.The solid was passed through silica gel column (100 g) eluting with 50%ethyl acetate in hexane followed by 10% methanol in methylene chlorideto provide 1.83 g (94.3%) of the title compound (fraction 11) and 400 mgof the corresponding sulfone (fraction 4-6). The product wascrystallized by dissolving in hot methanol and then chilling the solventto -78° C.; m.p. 103°-103.5° C.

d)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methylsulfonylmethyl)isoxazole.[R₁ =CH₃ S(O₂)CH₂, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen].

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methylsulfinomethyl)isoxazole(0.65 g, 1.47 mmol), 1.47 g of Al₂ O₃, 2.7 g of oxone, and 5 ml ofchloroform were combined under nitrogen at room temperature. The mixturewas heated to gentle reflux for 10 h, and allowed to stand at roomtemperature for 48 h. The mixture was filtered and the filtrateconcentrated in vacuo to provide 680 mg of a white solid. The productwas crystallized by dissolving in hot methanol and cooling the solvent,m.p. 122.5°-123° C.

EXAMPLE 52

a) 3-[Bromomethyl)-5-[3-(t-butyldiphenylsilyloxy)-propyl]isoxazole.

To a solution of triphenylphosphine in 10 ml of methylene chloride,chilled to -20° C., was added dropwise 1.52 g of bromine in 5 ml ofmethylene chloride till the reaction mixture just turned yellow. Themixture was titrated back to the endpoint with a few flakes oftriphenylphosphine. To the above solution was added dropwise 3.11 g(7.86 mmol) of3-(hydroxymethyl)-5-[3-(t-butyldiphenyl-silyloxy)propyl]isoxazole in 5ml of methylene chloride over a 10 min period and the mixture wasstirred for 15 min. The mixture was partitioned between 20 ml of waterand 50 ml of ether, and the aqueous layer was extracted twice withether. The combined organic layer was washed with brine, dried overmagnesium sulfate, and filtered. The filtrate was diluted with an equalvolume of hexane, passed through a pad of silica gel 60, and silica gelwas washed with 50 ml of ether/hexane (1:1). The combined filtrate wasconcentrated in vacuo to provide 3.38 g (93.9%) of the title compound asa clear colorless oil.

b)3-(Dimethylaminomethyl]-5-[3-(t-butyldiphenylsilyloxy)-propyl]isoxazole.

To a solution of3-(bromomethyl)-5-[3-(t-butyldiphenylsilyloxy)propyl]isoxazole (4.69 g,10.23 mmol) in 10 ml of N-methylpyrrolidinone was added under nitrogen2.31 g of dimethylamine (40% aqueous solution, 20.46 mmol). The reactionwas slightly exothermic. The mixture was diluted with water andextracted with ethyl acetate (3×). The organic layer was washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to provide 3.84 g (88.9%) of the title compound asa pale yellow oil.

c) 3-(Dimethylaminomethyl)-5-[3-(hydroxy)propyl]isoxazole.

3-(Dimethylaminomethyl)-5-[3-(t-butyldiphenylsilyloxy)propyl]isoxazole(3.84 g, 9.09 mmol) and 48 ml of THF were combined under nitrogen withstirring and 18.17 g (18.17 mmol) of TBAF (1M in THF) was added in oneportion. The reaction mixture (yellow) was stirred at room temperaturefor 30 min, diluted with water, and extracted with ethyl acetate (3×).The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated to provide 3.31 g of a yellow oil.This oil was passed through a silica gel 60 column (2.5×13 cm) elutingwith ethyl acetate, followed by 1% isopropylamine in ethyl acetate toafford 520 mg (31.1%) of the title compound.

d)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(dimethylaminomethyl)isoxazole.[R₁ =dimethylaminomethyl, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen].

Diethyl azodicarboxylate (DEAD, 230 mg) in 5 ml of THF was addeddropwise over a 5 min period to a chilled (0° C.) and stirring solutionof 3-(dimethylamino-methyl)-5-[3-(hydroxy)propyl]isoxazole (230 mg, 1.23mmol), 350 mg (6.23 mmol) of2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenol, and 350mg of triphenylphosphine in 7 ml of THF. The mixture was stirred at 0°C. for 15 min and then at room temperature for 30 min. An additionaltriphenylphosphine (70 mg, 0.25 ml) and DEAD (40 mg) were added to themixture and stirred at room temperature overnight. The mixture wasdiluted with water, extracted with ethyl acetate (3×), and the organiclayer was washed with water, brine, and dried over magnesium sulfate.The organic solution was concentrated in vacuo, the residue (1.01 g, apale green oil) was passed twice through a silica gel 60 column (1.5×15cm), eluting with ethyl acetate, followed by 5% methanol in ethylacetate to provide 560 mg of a yellow oil. MPLC (120 g Silica Gel 60, 3%methanol in ethyl acetate, 20 ml/min) provided 440 mg of pure titlecompound as a yellow oil. The oil was repurified by MPLC (120 g SilicaGel 60, 5% ethyl acetate in hexane, 20 ml/min), and the product in 0.5ml of methylene chloride was filtered through a cotton plug,concentrated in vacuo (35° C./32 mm/4 h) to provide 284 mg of the titlecompound.

EXAMPLE 53

a) 5-Acetoxyl-1-pentyne.

Acetic anhydride (11.26 g, 110 mmol) was added dropwise with stirring atroom temperature to a mixture of 4-pentyne-1-ol (8.24 mmol) and 8.26 gof pyridine (104 mmol), the reaction mixture was allowed to stand atroom temperature for 18 h and then heated at 50°-60° C. for 15 min. Themixture was poured into water, extracted with chloroform, and theorganic layer was washed with 1M HCl solution and 1.5M KHCO₃ solution,and the organic layer was dried over sodium sulfate. The chloroformsolution was concentrated in vacuo to provide 13.9 g of the titlecompound.

b) 3-(ethoxycarbonyl)-5-[(3-acetoxylpropyl]isoxazole.

5-Acetoxy-1-pentyne (13.9 g, 100 mmol) , ethyl nitroacetate (11.8 g,85.6 mmol) , and 0.5 ml of triethylamine were combined in 100 ml oftoluene, and 20,4 g (171.2 mmol) of phenylisocyanate was added at roomtemperature over a 15 min period. The mixture was stirred at roomtemperature for 1 h, heated near reflux (105° C.) for 3.5 h, and cooled.The mixture was diluted with ether, washed with 1M HCl solution and 1.5MKHCO₃ solution, and the organic layer was dried over sodium sulfate. Theorganic solution was concentrated in vacuo to provide an amber oil(approx. 30 g) which was purified by silica gel column chromatography(2.5×10, 5-20% ethyl acetate in hexane) followed by Kugelrohrdistillation (2×: 0.1 mm/heat gun) to provide 5.41 g of the titlecompound.

c) 3-(Hydroxymethyl)-5-[(3-acetoxy)propyl]isoxazole.

A solution of 3-(ethoxycarbonyl)-5-[(3-acetoxy)propyl]isoxazole (9b,5.1965 g, 21.5 mmol) in 25 ml of absolute ethanol, chilled in an icebath, was added 1.03 g (27.2 mmol) of sodium borohydride portionwise(gas evolution). The reaction mixture was quenched by pouring intoice/methylene chloride, washed with 1M HCl solution (3×) and water, anddried over sodium sulfate. The mixture was filtered and the filtrate wasconcentrated in vacuo to provide 1.82 g of a yellow oil.

d) 3-(Mesyloxymethyl)-5-[(3-acetoxy)propyl]isoxazole.

Triethylamine (1.85 g, 18.28 mmol),3-(hydroxymethyl)-5-[(3-acetoxy)propyl]-isoxazole (9c; 1.82 g, 9.14mmol) were combined and chilled in a dry ice/iso-propanol. To thissolution was added 1.57 g (13.7 mmol) of mesyl chloride in 10 ml ofmethylene chloride over a 30 min period, and the mixture was allowed towarm to room temperature overnight. The mixture was poured into water,the aqueous layer was extracted with methylene chloride (2×), and thecombined organic layer was washed with 1.5M KHCO₃ solution and driedover sodium sulfate. The solvent was concentrated in vacuo to provide2.33 g (92%) of the title compound.

e) 3-(Cyanomethyl)-5-[(3-acetoxy)propyl]isoxazole,

To a solution of 3-(mesyloxymethyl)-5-[(3-acetoxy)propyl]isoxazole (9d;2.33 g, 8.4 mmol) in 50 ml of N-methylpyrrolidinone was added 2.05 g (42mmol) of sodium cyanide and the mixture was stirred at room temperatureovernight. The mixture was poured into water, extracted with ether, andthe organic layer was concentrated in vacuo to provide 1. 52 g of thetitle compound which was purified by passing through a pad of silica gel(1×1.5) eluting with 10% ether/hexane followed by ether.

f) 3-(Cyanomethyl)-5-[(3-hydroxy)propyl]isoxazole.

To a solution of 3-(cyanomethyl)-5-[(3-acetoxy)propyl]isoxazole (9e; 810mg) in 50 ml of methanol was added 24 mg of sodium methoxide and themixture was stirred at room temperature overnight. The mixture waspoured into ice/water, extracted with methylene chloride, the organiclayer was concentrated in vacuo to provide an amber oil. The oil waspassed through a plug of silica gel eluting with ether to provide 10.2mg of of the title compound, m.p. 51°-52° C.

g)[2,6-Dimethyl-1-(cyclopropylcarboxy)-4-[(5-cyclopropyl)-1,2,4-oxadiazol-3-yl]benzene.

To a solution of N-hydroxy-3,5-dimethyl-4-hydroxyphenylcarboximidamide(1.77 g, 8.8 mmol) in pyridine was added dropwise via syringe 3.7 g (35mmol) of cyclopropylcarboxylic acid chloride and the mixture was allowedto stand overnight. The reaction mixture was diluted with ether, pouredinto ice/water, and the organic layer was filtered and washed with 1MHCl solution, water, and KHCO₃ solution. The organic solution was driedover sodium sulfate, concentrated in vacuo to provide a semisolid whichwas triturated in ether and filtered to remove insoluble solids. Thefiltrate was concentrated to provide 2.36 g of an oil which was dried at40° C./0.1mm; m.p. 178°-184° C. The above amidine was suspended intoluene, the mixture was refluxed for 23 h, and the solvent wasconcentrated in vacuo to yield a solid which was recrystallized frommethanol to provide 270.8 mg (54%) of the title compound, m.p. 89°-90°C.

h) [2,6-Dimethyl4- [(5-cyclopropyl) -1,2,4-oxadiazol-3-yl]phenol

To a solution of the product of 53(g) above (258 mg, 0.81 mmol) in 10 mlof methanol was added 52 mg of NaOH and the reaction mixture was stirredat room temperature overnight. The mixture was concentrated in vacuo,the residue was diluted with water/methylene chloride, the mixture wastreated with aqueous ammonium chloride solution. The organic layer wasfiltered through a pad of silica gel eluting with methylene chloride toprovide the title compound as a white solid, m.p. 94.5°-95.5° C.

i)5-{3-[2,6-Dimethyl-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyyl-3-(cyanomethyl)isoxazole.

[R₁ =cyanomethyl, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =cyclopropyl, R₅=hydrogen].

[2,6-Dimethyl-4-[(5-cyclopropyl)-1,2,4-oxadiazol-3-yl]phenol (172.3 mg,0.748 mmol), 3-(cyanomethyl)-5-[(3-hydroxy)propyl]isoxazole (112.9 mg,0.679 mmol), and 197.5 mg (0.735 mmol) of triphenylphosphine werecombined under argon in 2 ml of THF. To the above mixture, chilled inice/water bath, was added DEAD (128 mg, 0.735 mmol) in 2 ml of THF andthe mixture was stirred for 24 h. The mixture was poured into water,extracted with ether (3×), and the organic layer was dried overmagnesium sulfate and filtered. The organic solution was concentrated invacuo and the residue was passed through a silica pad (1×1.75) elutingwith 20-60% ether/hexane followed by ether to provide 120 mg of thetitle compound. The product was recrystallized from methanol; m.p.78°-78.5° C.

j) According to the method of Example 53; using appropriate startingmaterials,5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(cyanomethyl)isoxazole,(R₁ =cyanomethyl, R₂, R₃ =2,6-dimethyl, R₄ =trifluoromethyl, R₅=hydrogen, Y=1,3-propylene), m.p. 85°-85° C. was prepared.

EXAMPLE 54

a)5-{3-[2,6-Dimethyl-4-(5-difluorochloromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =difluorochloromethyl,R₅ =hydrogen].

3,5-Dimethyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxybenzene-carboximidamide(1.14 g, 3.78 mmol) was dissolved in 3.8 ml of pyridine with stirringunder nitrogen, and 1.31 ml (7.54 mmol) of ethyl difluorochloroaceticanhydride was added rapidly dropwise at a rate to cause the reactiontemperature to reach just below reflux. The mixture was stirred till itis cooled. The mixture was refluxed for 30 min, chilled in ice bath, andwas diluted with 50 ml of water. White solid product was collected byfiltration, washed with water (3×50 ml), dissolved in ethyl acetate, andthe solution was dried over magnesium sulfate. The solvent was passedthrough a pad of Florisil and concentrated in vacuo to provide 1.46 g ofa yellow oil. This oil was purified by silica gel 60 columnchromatography (1.5×10 cm, 20% ethyl acetate in hexane to provide 1.41 g(94 %) of a crystalline solid which was recrystallized from methanol toafford 1.29 g of the title compound, m.p. 58.5°-60° C.

b) 4-[3-(3-Methylisoxazol-5yl)propyloxy]phenylcyanide.

3-(3-Methylisoxazol-5yl)propyl chloride (9.58 g, 60 mmol) and 9 g (60mmol) of sodium iodide were combined in 75 ml of 2-butanone and themixture was refluxed with stirring for 30 min. To the above mixture 5.96g (50 mmol) of 4-cyanophenol and 13.8 g (0.1 mol) of potassium carbonatewere added, and the resulting mixture was refluxed overnight. The warmmixture was filtered. The residue was washed with acetone, the combinedfiltrate concentrated in vacuo, and the light oil residue wascrystallized from methanol to provide 5.43 g of the title compound, m.p.60°-61° C.

c)4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide.

4-[3-(3-Methylisoxazol-5yl)propyloxy]phenylcyanide (10b, 2.42 g, 10mmol), 3.48 g (50 mmol) of hydroxylamine hydrochloride, and 6.9 g ofpotassium carbonate were combined in 25 ml of ethanol with stirring andthe mixture was refluxed under nitrogen overnight. The mixture wasfiltered, the filtrate concentrated in vacuo, and the solid residue wastriturated in water and recrystallized from isopropyl acetate to provide2.17 g of the title compound, m.p. 124°-126° C.

d)5-{3-[4-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂) 3, R₂ and R₃ =H, R₄ =cyclohexyl, R₅ =hydrogen].

Cyclohexylcarboxylic acid chloride (1.2 ml, 9.3 mmol) was added neat toa stirred solution of4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide(1.28 g, 4.65 mmol) in 5 ml of pyridine (exothermic reaction) and themixture was refluxed for 1 h and cooled. The mixture was diluted withwater, solid product was washed with water and dissolved in methanol.The methanol solution was passed through a plug of silica gel, elutingwith methylene chloride, and the desired title compound (840 mg, 49%)was obtained after recrystallization from methanol: m.p. 100°-101° C.

e)5-{3-[4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =H, R₄ =cyclobutyl, R₅ =hydrogen].

Cyclobutylcarboxylic acid chloride (0.92 g, 7.77 mmol) was added neat toa stirred solution of4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide(1.07 g, 3.89 mmol) in 5 ml of pyridine (exothermic reaction) and themixture was refluxed for 1 h and cooled. The mixture was diluted withwater, extracted with methylene chloride, and the organic layer waswashed with dilute HCl solution, dilute NaOH solution and water, anddried over magnesium sulfate. The solution was passed through a plug ofsilica gel column, eluting with 10% ethyl acetate in methylene chloride,and the desired title compound (840 mg, 64%) was obtained aftercrystallization from methanol: m.p. 59°-60° C.

EXAMPLE 55

a) 4-Methoxy-3-methylbenzaldoxime.

3-Methyl-p-anisaldehyde (60 g, 0.33 mol), hydroxylamine hydrochloride(46.27 g, 0.666 mol), 50.02 g of pyridine, and 400 ml of absoluteethanol were combined with stirring under nitrogen, and the reactionmixture was refluxed for 2 h and cooled. The mixture was diluted withwater, stirred for 1 h, and the pale yellow solid was filtered, washedwith water and air dried. The solid product was dissolved in methylenechloride, the solution was dried over magnesium sulfate, and the solventwas concentrated in vacuo to provide 51.6 g (93.8%) of the titlecompound as a pale yellow solid.

b) 4-Methoxy-3-methylphenylcyanide.

4-Methoxy-3-methylbenzaldoxime (11a; 51.5 g, 0.3118 mol), 59.75 g(0.3685 mole) of 1,1'-carbonyldiimidazole, 250 ml of methylene chloridewere combined with stirring under nitrogen, and the mixture was refluxedovernight. The mixture was cooled, washed with 3N HCl, water, and brine,and the organic layer was dried over magnesium sulfate. The methylenechloride solution was filtered through florisil and concentrated invacuo to provide 44.9 g (97.8%) of the title compound as a pale yellowsolid.

c) 4-Hydroxy-3-methylpheny]cyanide.

To a solution of 4-methoxy-3-methylphenylcyanide (11b,44.8 g, 0.3044mol) in 150 ml of methylene chloride, chilled to 0° C. with stirringunder nitrogen, was added 575 ml (0.575 mol) of boron tribromide (1M inmethylene chloride) in a steady stream, and the mixture was stirred atroom temperature for 24 h. The reaction mixture was refluxed overnight,additional boron tribromide (44.7 ml) was added at 25° C. and themixture was stirred at room temperature for 30 min, refluxed for 3 h,and then stirred at room temperature for 48 h. Tlc indicated thepresence of the starting nitrile, and therefore, the third addition ofboron tribromide (60.88 ml) was made and the mixture was refluxedovernight. The reaction mixture was chilled to 0° C. in an ice bath, 175ml of methanol was added dropwise, and 600 ml of water was added. Theresulting mixture was stirred overnight. The aqueous layer was extractedwith methylene chloride (2×), the organic layer was washed with 10% NaOHsolution (3×). The basic aqueous layer was acidified to pH=5 with 6N HClsolution (product oiled out), the mixture was extracted with methylenechloride(3×), and the organic layer was washed with brine and dried overmagnesium sulfate. The methylene chloride solution was filtered throughFlorisil and concentrated in vacuo to provide 38.2 g of the titlecompound as a pale yellow solid, m.p. 95.5°-97° C.

d) 3-Methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-phenylcyanide,

3-(3-Methylisoxazol-5yl) propyl chloride (2.7 g, 16.9 mmol) and 0.2 g(60 mmol) of potassium iodide, 3.89 g (28.2 mmol) of potassium carbonate(milled, 80%), 2.7 g g (16.9 mmol) of 2-methyl-4-cyanophenol werecombined in 15 ml of N-methyl-2-pyrrolidinone with stirring and themixture was heated to 60° C. overnight. The mixture was diluted withwater, extracted with ethyl acetate (3×), and the organic layer waswashed with 10% NaOH solution, water, and brine, and dried overmagnesium sulfate. The ethyl acetate solution was filtered throughFlorisil and concentrated in vacuo to provide 3.64 g of a pale yellowsolid. The solid was repurified by MPLC (430 g Silica Gel 60, 20% ethylacetate in hexane, 25 ml/min) to provide 2.88 g (99.3%) of the titlecompound as a crystalline solid; m.p. 65°-66° C.

e)3-Methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide.

3-Methyl-4- [3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide (11d, 2.35g, 9.3 mmol), 3.19 g of hydroxylamine hydrochloride, and 6.33 g ofpotassium carbonate were combined in 45 ml of ethanol with stirringunder nitrogen, and the mixture was refluxed under nitrogen for 24 h.The mixture was filtered while warm and the filtrate concentrated invacuo to provide 2.74 g of the title compound as a pale yellow solid.

f)5-(3-[2-methyl-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole[R₁ =CH₃, y=(CH₂)₃, R₂ and R₃ =H, R₄ =cyclopropyl, R₅ =hydrogen].

3-Methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzene-carboximidamide(2.7 g, 9.9 mmol) was added to 5 ml of pyridine with stirring undernitrogen and 1.95 g (18.7 mmol) of cyclopropylcarbonyl chloride wasadded dropwise, and the resulting mixture was stirred 15 min, heated at65° C. overnight, and heated at 75° C. for 5 h. The reaction mixture wascooled, diluted with water, and stored in freezer. The aqueous layer wasdecanted and the gummy solid was washed with water. The solid wasdissolved in methylene chloride, dried over magnesium sulfate, filteredthrough silica and Florisil, and concentrated in vacuo to provide 3.79 gof a yellow oil. The oil was purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to afford 1.24 gof the title compound, which upon drying at 49° C./0.001 mm. yielded 920mg of white needles, m.p. 60°-62° C.

EXAMPLE 56

a) Tetrahydro-2-(4-pentynyloxy)pyran.

4-Pentyne-1-ol (8.41 g, 100 mmol), 13.7 ml (150 mmol) of3,4-dihydro-2H-pyran, 2.5 g (10 mmol) of pyridinium p-tosylate, and 100ml of methylene chloride were combined with stirring under nitrogen andthe mixture was stirred at room temperature for 1 h. The mixture waspartitioned between 100 ml of water and 150 ml of ether, the organiclayer was washed with 100 ml of water and brine, and dried overmagnesium sulfate. The ether solution was filtered through a plug ofsilica and concentrated in vacuo to provide 17.77 g of a pale yellowliquid. The oil was purified by flash silica gel (250 g) columnchromatography, eluting with 10 % ethyl acetate in hexane to afford14.75 g (87.8 %) of the title compound as a pale yellow oil.

b) Ethyl chloroximidoacetate (5.4 g, 35.6 mmol) was dissolved in 12 mlof N-methyl-2-pyrrolidinone (NMP) wth stirring under nitrogen, and thesolution was chilled to 0° C. in an ice bath. To the above solution wasadded dropwise tetrahydro-2-(4-pentynyloxy)pyran (2 g, 11.9 mmol) in 10ml of NMP over a 25 min period. The reaction mixture was heated to 85°C., 4.97 ml of triethylamine in 20 ml of NMP was added dropwise over an1 h period, and the mixture was heated (85° C.) for an additional 15min. The mixture was cooled, diluted with 100 ml of water, extractedwith ethyl acetate (3×), and the organic layer was washed with water andbrine, and dried over magnesium sulfate. The organic solution was passedthrough a pad of Florisil and concentrated in vacuo to provide an orangeoil (4.95 g) which was purified by filtering through a pad of silica gel(50% ethyl acetate in hexane) followed by MPLC (120 g Silica Gel 60, 15%ethyl acetate in hexane, 25 ml/min) to provide 1.69 g (fraction 29-47)of the desired compound as a clear oil.

c) The compound of 56b, (1.4 g (0.508 mmol) and 10 ml of aceticacid/water (1:1) were combined with stirring, and the mixture was heatedat 60° C. for 3 h, cooled, and diluted with water. The mixture wasdiluted with water, extracted with ethyl acetate (3×), and the organiclayer was washed with brine and dried over magnesium sulfate. The ethylacetate solution was concentrated in vacuo to provide 920 mg of a paleyellow oil which was purified by MPLC (120 g Silica Gel 60, 20% ethylacetate in hexane, 25 ml/min) affording 0.5 g (50%) of a compound offormula I (R₁ =phenoxycarbonyl, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄=trifluoromethyl, R₅ =hydrogen).

d) The compound of formula I (R₁ =carboxy, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =trifluoromethyl, R₅ =hydrogen).3-(phenoxycarbonyl)-5-[3-(hydroxy)propyl]isoxazole from example 56c(0.42 g, 2.1 mmol), 0.6 g (2.32 mmol) of2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenol, and 0.61g of triphenylphosphine were combined in 10 ml of THF under nitrogenwith stirring. The mixture was chilled to 0° C. and 0.4 g of diethylazodicarboxylate (DEAD) in 15 ml of THF was added dropwise over a 30 minperiod. The mixture was diluted with water, extracted with ethylacetate, and the organic layer was washed with water, 10% NaOH solution,water, brine, and dried over magnesium sulfate. The organic solution wasconcentrated in vacuo to provide 1.51 g of a yellow solid which waspurified by flash chromatography (100 g silica gel 60, 20% ethylacetate) to afford 520 mg of a white solid. The solid product wasrecrystallized from ethanol and dried (44° C./0.001 mm) to afford 170 mgof a white solid, m.p. 70°-71° C.

e) The compound of formula I (R₁ =carboxy, Y=(CH₂)₃, R₂ and R₃=2,6-dimethyl, R₄ =trifluoromethyl, R₅ =hydrogen)5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-(ethoxycarbonyl)isoxazole(520 mg, 11.8 mmol) was suspended in 15 ml of ethanol/water(9:1) and 38mg (15.74 mmol) of LiOH was added, and the resulting mixture was stirredat room temperature overnight. The mixture was diluted with water,extracted with ether (3×). The aqueous layer was acidified with glacialacetic acid, extracted with ether, and the organic layer was washed withbrine and dried over magnesium sulfate. The solvent was concentrated invacuo and the oil residue was thoroughly washed with cold water,dissolved in ethyl acetate/hexane, and dried over magnesium sulfate. Thesolvent was concentrated in vacuo to provide 407 mg of a white solidwhich was recrystallized from ethanol to afford 313 mg of the titlecompound, m.p. 138.5°-140.5° C.

EXAMPLE 575-{3-[2,6-Dimethyl-4-15-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-(methyl)-4-(bromo)isoxazole.

[R₁ =methyl, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =trifluoromethyl, R₅-bromo].

5-{3-[2,6-Dimethyl-4-(5-trifluoromethyl-1,2,4-oxadisazol-3-yl)phenoxy]-propyl}-3-methylisoxazole(690 mg, 1.8 mmol), 0.1 ml (2.0 mmol) of bromine, and 2 ml of glacialacetic acid were combined with stirring, and the mixture was stirred atroom temperature for 2 days. Additional bromine (0.1 ml) was added, themixture was stirred at room temperature for three more days. The mixturewas diluted with water, the solid product was filtered, washed withwater, and recrystallized from methanol to provide 680 mg of the titlecompound, m.p.79°-80°

EXAMPLE 58 a)5-{3-[2,6-Dimethyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =OH, R₅ =hydrogen].

To a mixture of3,5-dimethyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide(3.03g, 10 mmol) and potassium carbonate (1.52 g, 11 mmol) in 30 ml ofacetone, cooled to 0° C. under nitrogen, was added dropwise a solutionof ethyl chloroformate (1.05 ml, 11 mmol) in 5.5 ml of acetone and themixture was stirred at 0° C. for 1 h, and then at room temperature forovernight. The mixture was poured into water, the aqueous layer wasextracted with methylene chloride, and the organic layer was washed withbrine, and dried over magnesium sulfate. The organic solution wasfiltered through Florisil and concentrated in vacuo to provide a yellowsolid. The solid product was heated slowly to 130° C. in vacuo for 70min during which time the product melted and resolidified. The productwas washed with ether and dried in vacuo overnight to afford 2.51 g(76.3%) of the title compound, as a light tan solid. The product wasrecrystallized from methanol, m.p. 194°-5° C.

b)5-{3-[2,6-dimethyl-4-(5-chloro-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =Cl, R₅ =hydrogen].

Dry pyridine (0.59 ml ,7.5 ml) was added to 7 ml (75 mmol) ofphosphorous oxychloride. To the mixture was added5-{3-[2,6-dimethyl-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole(2.47 g, 7.5 mmol) and the resulting mixture was heated at 128° C. for 7h. The mixture was cooled in an ice bath, poured onto 125 ml of crushedice. After the excess POCl₃ is destroyed, the mixture was extracted withethyl acetate (2×50 ml), and the organic layer was washed with saturatedsodium bicarbonate solution and brine, and dried over magnesium sulfate.The solvent was concentrated in vacuo and the residue was dissolved inmethylene chloride, filtered through Florisil, and concentrated in vacuoto provide 2.34 g of the title compound as a yellow oil. MPLC (silicagel 60, 26×460 mm, 12% ethyl acetate in hexane, 20 ml/min) provided 2.13g (81.6%) of the title compound, m.p. 71°-71° C.

c)5-{3-[2,6-Dimethyl-4-(5-sulfo-4,5-dihydro-1-2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =SH, R₅ =hydrogen].

To a suspension of sodium hydride (48 mg, 7.5 mmol) in dry, degassedN-methylpyrrolidione was condensed methanethiol. Gas evolution wasobserved. To this solution was added dropwise a solution of5-{3-[2,6-dimethyl-4-(5-chloro-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole(348 mg,1 mmol) in 2 ml of dry and degassed NMP. After 2 h, the mixturewas poured into 25 ml of of saturated ammonium chloride solution andwashed with ether (2×25 ml). The aqueous layer was acidified with conc.HCl solution and the solid product was filtered, washed with water andether, and air dried to provide 251 mg of the title compound as a whitepowder, m.p. 162°-165° C. (d).

d)5-{3-[2,6-dimethyl-4-(5-methylthio-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole.[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =methyl-thio, R₅=hydrogen].

5-{3-[2,6-Dimethyl-4-(5-thio-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole(0.35 g, 1 mmol) and 0.17 g (1.2 mmol) of potassium carbonate werecombined in 3.5 ml of acetone with stirring under nitrogen. The mixturewas chilled to 0° C. in an ice bath for 1 h and 0.156 g (1.1 mmol) ofmethyl iodide as added and the resulting mixture was stirred at 0° C.for 1 h. The mixture was diluted with 5 ml of water, extracted withether (3×), and the organic layer was washed with brine and dried overmagnesium sulfate. The ether solution was concentrated in vacuo toprovide a pale yellow solid (310 mg) which was purified by flash silicagel column (1.6×11, 50% ethyl acetate in hexane) chromatographyaffording 300 mg (83.3%) of the title compound.

EXAMPLE 595-{3-[2,6-dimethyl-4-(5-methylthiomethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-dimethyl, R₄ =methylthiomethyl, R₅=hydrogen].

Methanesulfide (15 drops condensed via cold finger at -78° C.) wascondensed into a stirred solution of 480 mg (0.96 mmol) of the compoundof example 42 and DIPEA (250 mg) in 10 ml of methylene chloride undernitrogen, and the mixture was stirred at room temperature for 1 h. Themixture was partitioned between 20 ml of water and 10 ml of ether, andthe aqueous layer was extracted with ether (3×). The combined organiclayer was washed with, brine, dried (MgSO₄), and passed through flashchromatography (silica gel, 1.6×23, 20% ethyl acetate in hexane) toprovide 360 mg (100%) of the title compound which was recrystallizedfrom methanol, m.p. 79.5°-80° C.

EXAMPLE 60 a) 4-Cyano-2-fluorophenol,

4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCNwere combined in 75 ml of NMP with stirring under nitrogen, and themixture was heated at 150° C. for 5 h. The mixture was diluted with 200ml of ether, stirred, and decanted. The residue was diluted again with200 ml of ether, heated, and decanted. The combined decantates werewashed with water, 1N HCl solution, water, and brine, and dried overmagnesium sulfate. The organic solution was concentrated in vacuo toprovide 12 g of a white solid which was triturated in carbontetrachloride and filtered to afford 7.29 g (72.1%) of the titlecompound.

b) 4-Cyano-2-fluoro-6-iodophenol

Potassium iodide (7.97 g, 48 mmol) was dissolved in 125 ml of DMF withstirring, and 4-cyano-2-fluorophenol (16a; 5.56 g 48 mmol) andchloramine-T in 75 ml of DMF were added dropwise with stirring. Thereaction mixture was poured into 650 ml of water, acidified with 6N HCl,and extracted with ethyl acetate. The organic layer was washed with 10%NaHSO₃, water and brine and dried over magnesium sulfate. The organicsolution was concentrated in vacuo and the yellow solid residue wastreated with 200 ml of 1N NaOH solution, filtered through supercel, andthe filtrate was acidified with conc. HCl solution. The solid productwas filtered, dried, dissolved in ether, and the organic layer was driedover magnesium sulfate. The organic solution was concentrated in vacuoand the residue was recrystallized from ethylene chloride to afford 5.93g (55.6%) of the title compounds.

c) 3-Fluoro-5-iodo-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide,

3-(3-Methylisoxazol-5yl)propyl chloride (4.65 g, 28 mmol), 6.35 g (46mmol) of potassium carbonate, 4.65 g (28 mmol) of potassium iodide, and5.93 g (30 mmol) of 2-fluoro-6-iodo-4-cyanophenol (16b) were combined in50 ml of N-methyl-2-pyrrolidinone with stirring, and the mixture washeated at 110° C. for 2h and stirred at room temperature overnight. Themixture was diluted with 2N NaOH solution, stirred, filtered and driedto provide a tan solid. The product was filtered through a plug ofsilica gel with methylene chloride and the solvent was concentrated invacuo to provide 7.91 g of a yellow oil. The product was crystallizedfrom methanol and purified by MPLC (silica gel 60, hexane/ethyl acetate(8:2) to afford 7.04 g of the title compound as a white solid,m.p.69°-70° C.

d)3-Fluoro-5-iodo-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzenecarboximidamide.

3-Fluoro-5-iodo-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide (16c,1.16 g, 3 mmol), 1.04 g (15 mmol) of hydroxylamine hydrochloride, and2.07 g of potassium carbonate were combined in 50 ml of absolute ethanolwith stirring , and the mixture was refluxed for 12 h. The mixture wasfiltered and the filtrate concentrated in vacuo to provide 1.95 g of thetitle compound as a white solid. The product was triturated in 75 ml ofether, filtered through Florisil and concentrated to afford 1.17 g (93%)of the title compound as viscous oil.

e)5-{3-[2-Fluoro-6-iodo-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2-fluoro-6-iodo, R₄ =trifluoromethyl, R₅=hydrogen].

3-Fluoro-5-iodo-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzene-carboximidamide(16d;613 mg, 1.46 mmol) was dissolved in 2 ml of pyridine with stirring undernitrogen and heated to 85° C. in an oil bath. To the above solution 0.6ml (4.25 mmol) of trifluoroacetic anhydride was added dropwise and themixture was stirred for 1 min at 85° C. and cooled. The mixture wasdiluted with water, the white solid product was collected by filtrationand recrystallized from methanol to afford 280 mg of the title compound,m.p. 79°-80° C.

f) 3-Fluoro-5-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide.

3-Fluoro-5-iodo-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide (3.86g, 1 mmol), 1.7 ml (12 mmol) of tetramethyltin, 300 mg (0.43 mmol) ofbis(triphenylphosphine)palladium chloride, and 50 ml ofN-methyl-2-pyrrolidinone were combined with stirring under nitrogen, andthe mixture was heated at 120° C. for 2 h and cooled. The mixture waspoured directly onto a large plug of silica gel moistened with methylenechloride and eluted with methyene chloride. The organic solution waswashed with water and brine, and the organic layer was dried overmagnesium sulfate, filtered, and concentrated to provide 3.8 g of anorange oil. The product was crystallized from water, triturated andrecrystallized from methanol to afford 2.3 g (84%) of the title compoundas a yellow solid, m.p.42°-43° C.

g)3-Fluoro-5-methyl-4-[3-(3-methylisoxazol-5yl]propyloxy]-N-hydroxy-benzenecarboximidamide.

3-Fluoro-5-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide(16f, 1.05 g, 3.83 mmol), 1.32 g (19 mmol) of hydroxylaminehydrochloride, and 2.63 g (19 mmol) of potassium carbonate were combinedin 50 ml of absolute ethanol with stirring , and the mixture was stirredat room temperature for 16 h. The mixture was filtered and the filtrateconcentrated in vacuo to provide 1.31 g of the title compound as a whitesolid. The product was triturated in water, filtered, and dried toprovide 1.13 g (96%) of the title compound as a white solid, m.p.135°-137° C.

h)5-{3-[2-Fluoro-6-methyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2-fluoro-6-methyl, R₄ =trifluoromethyl,R₅ =hydrogen].

3-Fluoro-5-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]-N-hydroxy-benzene-carboximidamide(16g; 500 mg, 1.63 mmol) was suspended in 2 ml of pyridine at roomtemperature with stirring under nitrogen. To the above solution wasadded dropwise 0.35 ml (2.5 mmol) of trifluoroacetic anhydride(exothermic reaction) and the resulting mixture was refluxed for 2 h.The mixture was partitioned between water and ether, the organic layerwas washed with 1N HCl solution, water, and brine, and dried overmagnesium sulfate. The organic solution was concentrated in vacuo andthe residue was filtered through a plug of silica gel eluting withmethylene chloride to provide 300 mg (48%) of the title compound, as awhite solid, m.p. 45°-46° C.

EXAMPLE 61

a) 2-Chloro-4.6-diiodophenol.

Sodium iodide (5.4 g, 15 mmol) in 100 ml of DMF was heated to 40°-50° C.and the resulting solution was cooled to room temperature. To the abovesolution 8.93 g (30 mmol) of chloramine-T was added. After 15 min, anadditional 5 mmol of chloramine-T was added and the mixture was allowedto react at room temperature for 1 h. The reaction mixture wasconcentrated in vacuo, the residue was suspended in 300 ml of water,filtered and the filtrate was acidified with conc. HCl solution to pH2-3. The solid product and aqueous layer was extracted with ethylacetate (3×), the combined organic layer was dried (MgSO₄) andconcentrated in vacuo. The dark brown residue was disolved in methylenechloride, washed with sodium thiosulfate solution (2×), dried, andconcentrated in vacuo to provide a white solid. The solid product waspurified by silica gel column chromatography (20% ethyl acetate inhexane) to provide 5.45 g (96%) of the title compound as a white solid.

b) 2,4-Diiodo-6-chloro-4-[3-(3-Methylisoxazol-5yl]propyloxy]benzene.

3-(3-Methylisoxazol-5yl)propyl chloride (3 g, 7.9 mmol), 0.5 g ofpotassium iodide, 1.8 g (11.7 mmol) of 2,4-diiodo-6-chlorophenol, and2.7 g (19.8 mmol) of potassium carbonate were combined in 45 ml of NMPunder nitrogen, and the mixture was heated at 60° C. with stirring for3.5 h. The mixture was poured into water, acidified to pH 3-4 with 2NHCl solution, and extracted with ethyl acetate (3×). The combinedorganic layer was dried (MgSO₄), filtered, and concentrated to provide ayellow oil. The oil was dissolved in methylene chloride and purified bysilica gel chromatography (15% ethyl acetate in hexane) to provide 2.85g (72%) of the title compound as a white solid, m.p. 66°-68° C.

c) 2,4-Dicyano-6-chloro-4-[3-(3-Methylisoxazol-5yl)propyloxy]benzene.

2,4-Diiodo-6-chloro-4-[3-(3-Methylisoxazol-5yl)propyloxy]benzene (1.5 g,2.97 mmol) and 622 mg of CuCN were combined in 6 ml of DMF undernitrogen, and the mixture was heated at 120° C. for 7 h (during whichtime an additional 100 mg of CuCN added). The mixture was poured into100 ml of 2N HCl and 100 ml of ethyl acetate while stirring vigorouslyfor 1 h and filtered. The solid residue was partitioned (2×) again in100 ml of ethyl acetate/2N HCl (1:1). The aqueous layer was extractedwith ethyl acetate (3×), and the combined organic layer was dried(MgSO₄), and concentrated. The solid residue gas suspended in ether,filtered, and dried in vacuo to provide 539 mg (60%) of the titlecompound.

d)4-[3-(3-methylisoxazol-5yl)propyloxy]-2-cyano-6-chloro-N-hydroxybenzenecarboximidamide.

4-[3-(3-Methylisoxazol-5yl)propyloxy]-2,4-dicyano-6-chlorobenzene (17c,300 mg, 0.99 mmol), 124 mg (1.79 mmol) of hydroxylamine hydrochloride,and 683 mg (4.95 mmol) of potassium carbonate were combined in 10 ml ofethanol with stirring, and the mixture was refluxed under nitrogen for75 min. The mixture was filtered while hot, the residue was washed withhot ethanol and methylene chloride, and the filtrate concentrated invacuo to provide 320.4 mg (97%) of the title compound.

e)5-{3-[4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)2-cyano-6-chlorophenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ =CN, R₃ =Cl, R₄ =trifluoromethyl, R₅ =hydrogen].

Trifluoroacetic anhydride (0.328 ml, 2.4 mmol) was added neat to astirred solution of4-[3-(3-methylisoxazol-5yl)propyloxy]-2-cyano-6-chloro-N-hydroxy-benzenecarboximidamide(320.4mg, 0.95 mmol) in 3 ml of pyridine (exothermic reaction) and the mixturewas heated to 60°-70° C. for 1 h. The mixture was concentrated in vacuoto remove pyridine, and the residue was partitioned between water andethyl acetate. The aqueous layer was washed with ethyl acetate, and thecombined organic layer was washed with water, dried (MgSO₄), andconcentrated in vacuo. The solid residue was triturated in hexane andrecrystallized from hexane/ether (9:1) to provide 189 mg (48%) of thetitle compound, m.p. 70°-71° C.

EXAMPLE 62 a) 4-Iodo-2-methylphenol.

To a solution of 10 g of o-cresol and 16.5 g (1.2 equiv) NaI in 250 mlof DMF was added 31 g (1.2 equiv) of chloramine-T hydrate. The darkgreen solution was stirred at rt for 1.5 h. The mixture, now aheterogeneous light brown, was poured into water, acidified, extractedwith ethyl acetate, and the organic phase washed with water andbisulfite solution. The organic phase was dried over MgSO₄.Concentration, trituration with hexane, and flash chromatography (silicagel, hexane, hexane/ethyl acetate (5:1)) provided 13.6 g (63%) of thetitle compound as a white solid.

b) 4-Iodo-2-methylphenol.

To a solution of 15 g of o-cresol and 24.8 g of NaI in 400 ml of DMF wasadded 46.5 g of chloramine-T hydrate. The dark green solution wasstirred at rt for 1.5 h. The mixture, now a heterogeneous light brown,was poured into water, acidified, extracted with ethyl acetate, and theorganic phase washed with water and bisulfite solution. The orangeorganic phase was concentrated in vacuo and the product washedthoroughly with hexane to remove the product. The hexane wash wasconcentrated in vacuo and purified by flash chromatography (silica gel,hexane, hexane/ethyl acetate (4:1)) to provide 20.1 g (62%) of the titlecompound as a white solid.

c. 2,4-Diiodo-6-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]benzene,

3-(3-Methylisoxazol-5yl)propyl chloride (3.6 g, 10 mmol), 0.25 g ofpotassium iodide, 3.2 g (20 mmol) of 2,4-diiodo-6-methylphenol, and 4.4g of potassium carbonate were combined in 20 mi of NMP under nitrogen,and the mixture was heated at 60° C. with stirring for 3.5 h. Themixture was poured into water, acidified to pH 3°-4 with 2N HClsolution, and extracted with ethyl acetate (3×). The combined organiclayer was dried (MgSO₄), filtered, and concentrated to provide a yellowoil. The oil was dissolved in methylene chloride and purified by silicagel chromatography (12-15% ethyl acetate in hexane) followed bycrystallization from ethanol and drying at 0.44 mm to provide 2.72 g ofthe title compound as a white solid, m.p. 71.5°-73° C.

d) 2,4-Dicyano-6-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]benzene.

2,4-Diiodo-6-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]benzene (270mg, 0.56 mmol) and 130 mg of CuCN were combined in 0.7 ml of DMF undernitrogen, and the mixture was heated at 115° C. for 2 h. Water andmethylene chloride were added to the mixture, heated briefly, andfiltered (this process was repeated 3×). Ethyl acetate/water was addedto the residue, heated briefly, and filtered (this process wasrepeated). The combined organic layer was dried over MgSO₄,concentrated, and the residue was purified by flash chromatography(silica gel, 25% ethyl acetate in hexane) followed by ethanolcrystallization to provide 105 mg of the title compound as a whitesolid, m.p. 46°-48° C.

e)4-[3-(3-methylisoxazol-5yl)propyloxy]-2-cyano-6-chloro-N-hydroxy-benzenecarboximidamide.

4-[3-(3-Methylisoxazol-5yl)propyloxy]-2,4-dicyano-6-methylbenzene (18d,281 mg, 1 mmol), 175 mg (2.5 mmol) of hydroxylamine hydrochloride, and700 mg (5 mmol) of potassium carbonate were combined in 4 ml of ethanolwith stirring, and the mixture was refluxed (85°-95° C.) under nitrogenfor 4 h. The mixture was diluted with methylene chloride, filtered,triturated with methylene chloride/ethanol and filtered. The filtratewas concentrated in vacuo and the residue was dried to provide 330 mg ofthe title compound as a yellow gum.

f)5-{3-[4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)2-zyano-6-chlorophenoxy]-propyl}-3-methylisoxazole.

[R₁ =CH₃, Y=(CH₂)₃, R₂ =CN, R₃ =Cl, R₄ =cyclohexyl, R₅ =hydrogen].

To a stirred solution of4-[3-(3-methylisoxazol-5yl)propyloxy]-2-cyano-6-chloro-N-hydroxy-benzenecarboximidamide(330mg, 1 mmol) in 2.5 ml of pyridine was added trifluoroacetic anhydride(0.328 ml) was added dropwise over an 1 min period, and the mixture washeated at 60° C. for 1 h. The mixture was concentrated in vacuo toremove pyridine, and the residue was partitioned between ether and 1NHCl solution. The aqueous layer was extracted with ether (3×), and thecombined organic layer was washed with water and saturated sodiumbicarbonate solution, and dried (MgSO₄). The solvent was concentrated invacuo, the solid residue was purified by flash chromatography (silicagel, 20-25% ethyl acetate/hexane;) followed by recrystallization fromethanol to provide 182 mg (46%) of the title compound as a white solid,m.p. 63°-64° C. From an earlier fraction (flash chromatography), 6 mg of5-{3-[2,4-bis(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-6-chlorophenoxy]-propyl}-3-methyl-isoxazolewas obtained as a by-product.

EXAMPLE 63

a) 2-Methyl-4-cyano-6-methylphenol.

2-Chloro-4-bromo-6-chlorophenol (1 g, 4.5 mmol) and 600 mg of CuCN werecombined in 5 ml of DMF under nitrogen, and the mixture was heated at120° C. for 5 h. The mixture was partitioned between 2N HCl solution andethyl acetate, the aqueous layer was extracted with ethyl acetate (3×),and the combined organic layer was dried (MgSO₄) and concentrated toprovide a brown oil. The oil residue was dissolved in minimal methylenechloride and passed through silica gel column eluting with 10% ethylacetate in hexane to provide 210 mg (28%) of the title compound as awhite solid, m.p. 41°-42° C.

b)2-chloro-4-cyano-6-methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]benzene.

3-(3-Methylisoxazol-5yl)propyl chloride (143 mg, 0.9 mmol), 0.1 g ofpotassium iodide, 0.1 g (0.6 mmol) of 2-chloro-4-cyano-6-methylphenol,and 0.207 g of potassium carbonate were combined in 2 ml of NMP undernitrogen, and the mixture was heated at 60° C. with stirring overnight.The mixture was partitioned between water/ethyl acetate, the aqueouslayer was extracted with ethyl acetate (3×) and the combined organiclayer was dried over MgSO₄. The solvent was concentrated in vacuo, theyellow oil residue was dissolved in methylene chloride and passedthrough silica gel column eluting with 10-20% ethyl acetate in hexane toprovide 126 mg (72%) of the title compound as a white solid, m.p.100°-101° C.

c)4-[3-{3-methylisoxazol-5-yl)propyloxy]-2-chloro-6-methyl-N-hydroxy-benzenecarboximidamide.

2-Chloro-4-cyano-6-methyl-4-[3-(3-methylisoxazol-5-yl)propyloxy]benzene(19b, 4.2 g, 14 mmol), 1.8 g (26 mmol) of hydroxylamine hydrochloride,and 9.66 g (70 mmol) of potassium carbonate were combined in 100 ml ofethanol with stirring under nitrogen, and the mixture was refluxed for6.5 h. The mixture was filtered while hot, the residue was washed withhot ethanol. The filtrate was concentrated in vacuo to remove ethanol.The solid residue was dissolved in methylene chloride, filtered, andconcentrated in vacuo. The solid product was triturated with ether andfiltered to provide 4.06 g (90%) of the title compound as a white solid.

d)5-{3-[4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)2-chloro-6-methylphenoxy]propyl}-3-methylisoxazole.

[R₁ =Ch₃, Y=(CH₂)₃, R₂ =Cl, R₃ =methyl, R₄ =trifluoromethyl, R₅=hydrogen].

4-[3-(3-Methylisoxazol-5-yl)propyloxy]-2-chloro-6-methyl-N-hydroxy-benzenecarboximidamide(400 mg, 1.2 mmol) was dissolved at room temperature under nitrogen in 3ml of pyridine. To the above solution was added trifluoroaceticanhydride (0.423 ml, 3 mmol)) was added dropwise, and the mixture wasstirred at room temperature for 2 h. The residue was partitioned betweenwater/ether, the aqueous layer was extracted with ethyl acetate (3×).The combined organic layer was dried (MgSO₄), filtered and concentratedin vacuo to provide a yellow oil. The oil, in a minimum volume ofmethylene chloride, was purified by flash chromatography (silica gel,10% ethyl acetate/hexane) to provide 165 mg (34%) of the title compoundas a white solid, m.p. 55°-56.5° C.

EXAMPLE 64

Using the product of Example 18 and acetic anhydride there was prepared5-{3-[2,6-Dimethyl-4-(5-acetamido-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole,(R₁ =methyl, R₂, R₃ =2,6-dimethyl, R₄ =acedamido, R₅ =hydrogen,4=1,3propylene), m.p. 137°-138° C.

EXAMPLE 65

Using the method of Example 1a-e but substituting 3-methyl4-hydroxybenzonitrile for 3,5-dimethyl-4-hydroxybenzonitrile in 1c acompound of formula I (R₁ R₂ =methyl 1, R₃ =hydrogen, R₄=trifluoromethyl, R₅ =hydrogen, Y=1,3 propylene);5-{3-[2-methyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazole,m.p. 69°-70° C. was obtained.

EXAMPLE 66

Using the product of Example 1d, and reacting it with α,αdifluoropropionic andydride, one obtains a compound of formula I (R₁=methyl R₂, R₃ =2,6-dimethyl, R₄ =1,1 difluoroethyl, R₅ =hydrogen, Y=1,3propylene);5-{3-[2,6-Dimethyl-4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)phenoxy]-propyl}-3-methylisoxazolem.p. 64°-65° C.

Following a procedure similar to that of Example 1d but substituting forthe product from Example 1c an equivalent amount of the above compoundsof formula IX there can be obtained respectively the following compoundsof formula V:

4-[3-(3-methylisoxazol-5-yl)propyloxy]-3-nitro-N-hydroxybenzenecarboximidamide

3,5-dimethoxy-4-[3-(3-methylisoxazol-5-yl)propyloxy]-N-hydroxybenzenecarboximidamide

4-[3-(3-methylisoxazol-5-yl)propyloxy]-3-trifluoro-methyl-N-hydroxybenzenecarboximidamide.

EXAMPLE 67

Using a method substantially the same as the method of example 1a to 1e,but replacing 3,5 dimethyl-4-hydroxybenzonitrile in 1c with andequivalent molar amount of 3-methoxy-5-methyl-4-hydroxybenzonitrile, acompound of formula 1 (R₁ =methyl, R₂ =3-methoxy, R₃ =5-methyl, R₄=trifluromethyl, R₅ =hydrogen, Y=1,3 propylene)5-{3-[2-methoxy-6-methyl-4-(5-trifluoromethyl-1,2,4-oxadiazole-3-yl)phenoxy]propyl}-3-methylisoxazolewas obtained, m.p. 35.5°-37° C.

EXAMPLE 68

Using a method substantially the same as the method of example 1a to 1e,but replacing 3,5 dimethyl-4-hydroxybenzonitrile in 1c with andequivalent molar amount of 3-methoxy-5-methyl-4-hydroxybenzonitrile, andreplacing trifloroacetic anhydride with difluoroacetic anhydride in thestep described in example 1e a compound of formula 1 (R₁ =methyl, R₂=3-methoxy, R₃ =5-methyl, R₄ =difluoromethyl, R₅ =hydrogen, Y=1,3propylene)5-{3-[2-methoxy-6-methyl-4-(5-difluoromethyl-1,2,4-oxadiazole-3-yl)phenoxy]propyl)-3-methylisoxazolewas obtained, m.p. 71°-72° C.

The ethylnyl compound of formula XIII, from example 20a was acetylatedusing trifluoroacetyl chloride, and then was reacted with a twofoldexcess of hydroxylamine hydrochloride according to the method of example20 b. A compound of formula I was obtained substantially by the methodof 20c (R₁ =trifluoromethyl, R₂, R₃ =3,5-dimethyl, R₄ =trifluoromethyl,R₅ =hydrogen, Y=1,3 propylene),5-{3-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazole-3-yl)phenoxy]propyl}-3-trifluoromethylisoxazolem.p. 60°-61° C.

Following a procedure similar to that of Example 1e but substituting forthe product of Example 1d an equivalent amount of the above compounds offormula V there can be obtained respectively the following compounds offormula I:

3-methyl-5-{3-[2-nitro-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole[I; R₁ =Ch₃, Y=(CH₂)₃, R₂ =2-NO₂, R₃ =H, R₄ =CF₃, R₅ =hydrogen]

5-{3-[2,6-dimethoxy-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(OCH₃)₂, R₄ =CF₃, R₅ =hydrogen]

3-methyl-5-(3-[2-trifluoromethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole[I; R₁ =Ch₃, Y=(CH₂)₃, R₂ =2-CF₃, R₃ =H, R₄ =CF₃, R₅ =hydrogen].

Following the procedures of Example 20a, b and c and using equivalentamounts of reactants in each case but substituting in Example 20a11-chloro-1-undecyne for 5-chloro-1-pentyne there can be obtainedsuccessively the following:

3,5-dimethyl-4-(9-ethinylnonyloxy)benzonitrile;

3,5-dimethyl-4-(9-ethinylnonyloxy)-N-hydroxy-benzenecarboximidamide; and

3-[3,5-dimethyl-4-(9-ethinylnonyloxy)phenyl]-5-tri-fluoromethyl-1,2,4-oxadiazole.

Following Procedure 1 and using equivalent amounts of acetaldehyde oximeand3-[3,5-dimethyl-4-(9-ethinylnonyloxy)phenyl]-5-trifluoromethyl-1,2,4-oxadiazole,there can be obtained5-{9-[2,6-dimethyl-4-(5-trifluoro-methyl-1,2,4-oxadiazol-3-yl)phenoxy]nonyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₉, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CF₃, R₅ =hydrogen].

Following Procedure 1 and using equivalent amounts of n-hexyl aldehydeoxime and the product of Example 20c, there can be obtained5-{3-[2,6-dimethyl-4-(5-trifluoromethyl)phenoxy]propyl}-3-(n-pentyl)isoxazole[I; R₁ =(CH₂)₄ CH₃, Y=(CH₂)₃, R₁ and R₂ =2,6-(CH₃)₂, R₄ =CF₃, R₅=hydrogen].

Following the procedure of Example 37 but substituting an equivalentamount of n-pentyl bromide for the ethyl iodide, there can be obtained5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-pentyloxyisoxazole[I; R₁ =O(CH₂)₄ CH₃, Y=(CH₂)₃, R₁ and R₂ =2,6-(CH₃)₂. R₄ =cyclopropyl,R₅ =hydrogen].

Following the procedure of Example 37 but substituting equivalentamounts of the product of Example 40 and n-pentyl bromide for theproduct of Example 36b and ethyl iodide respectively, there can beobtained5-{3-[2,6-dimethyl-4-(5-(n-pentyloxymethyl)-1,2,4-oxadiazol-3-yl)-phenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₂ and R₃ =2,6-(CH₃)₂, R₄ =CH₂ O(CH₂)₄ CH₃, R₅=hydrogen].

Following the procedure of Example 1e but substituting an equivalentamount of cyclohexanecarbonyl chloride for the trifluoroaceticanhydride, there can be obtained5-{3-[4-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-methylisoxazole[I; R₁ =CH₃, Y=(CH₂)₃, R₁ and R₂ =2,6-(CH3)₂, R₄ =cyclohexyl, R₅=hydrogen].

Biological evaluation of representative compounds of formula I has shownthat they possess antiviral activity. They are useful in inhibitingvirus replication in vitro and are primarily active againstpicornaviruses, including enteroviruses, echovirus and coxsackie virus,especially rhinoviruses. The in vitro testing of the representativecompounds of the invention against picornaviruses showed that viralreplication was inhibited at minimum inhibitory concentrations (MIC)ranging from 0.002 to 9.608 micrograms per milliliter. The testprocedure used was as follows:

The MIC values were determined by an automated tissue culture infectiousdose 50% (TCID-50) assay. HeLa cells in monoloyers in 96-well clusterplates were infected with a dilution of virus which had been shownempirically to produce 80% to 100% cytopathic effect (CPE) in 3 days inthe absence of drug. The compound to be tested was serially dilutedthrough 10, 2-fold cycles and added to the infected cells. After a 3 dayincubation at 33° C. and 2.5% carbon dioxide, the cells were fixed witha 5% solution of glutaraldehyde followed by staining with a 0.25%solution of crystal violet in water. The plates were then rinsed, dried,and the amount of stain remaining in the well (a measure of intactcells) was quantitated with an optical density reader. The MIC wasdetermined to be the concentration of compound which protected 50% ofthe cells from virus-induced CPE relative to an untreated virus control.

In the above test procedures, representative compounds of formula I weretested against some the serotypes from either a panel of fifteen humanrhinovirus (HRV) serotypes, (noted in the table as panel T) namely,HRV-2, -14, -1A, -1B, -6, -21, -22, -15, -25, -30, -50, -67, -89, -86and -41 or against some of the serotypes from a panel of 10 humanrhinovirus serotypes namely HRV-3, -4, -5, -9, -16, -18, -38, -66, -75and -61, (noted in the table as panel B) and the MIC value, expressed inmicrograms per milliliter (mg/ml), for each rhinovirus serotype wasdetermined for each virus, example 1e is given as an example of thedata. Then MIC₅₀ and MIC₈₀ values, which are the minimum concentrationsof the compound required to inhibit 50% and 80%, respectively, of thetested serotypes were determined. The compounds tested were found toexhibit antiviral activity against one or more of these serotypes.

The MIC values (μg/ml) obtained for the compound of Example 1e in theabove-described antiviral test procedure were as follows:

                  TABLE I                                                         ______________________________________                                        HRV         HRV          HRV                                                  Serotype (MIC.sub.50)                                                                     Serotype (MIC.sub.50)                                                                      Serotype (MIC.sub.50)                                ______________________________________                                        - 2 (0.027) -21 (0.015)  -50 (0.154)                                          -14 (0.022) -22 (0.011)  -67 (0.070)                                          -1A (0.119) -15 (0.147)  -89 (0.015)                                          -1B (0.054) -25 (0.036)  -86 (0.029)                                          -6 not tested                                                                             -30 (0.047)  -41 (0.338)                                          ______________________________________                                        MIC.sub.50                                                                              MIC.sub.80  Panel   N                                               ______________________________________                                        0.0415    0.119       T       15                                              ______________________________________                                    

The following Table gives the test results for representative compoundsof the invention. The panel of viruses used in the test appears beforethe the MIC₈₀ and MIC₅₀ figure and the number of serotypes which thecompound is tested against (N) is indicated after the MIC₈₀ and MIC₅₀figure.

                  TABLE II                                                        ______________________________________                                        EX.    WIN       PANEL    MIC.sub.50                                                                            MIC.sub.80                                                                          N                                     ______________________________________                                         1e    63843     T        0.0415  0.119 15                                     4     63923     T        3.145   0.057 15                                     5     64173     T        0.153   0.037 15                                     6     64306     T        0.073   0.046 15                                     7     64174     T        99      99    14                                     8     64239     T        99      99    12                                     9     64228     T        0.279   0.141 14                                    10     65719     T        0.279   0.141 14                                    11     67483     T        1.9845  0.2485                                                                              12                                    12     64243     T        2.941   0.662 14                                    13     65996     T        0.266   0.145 14                                    14     66407     T        0.054   0.022 15                                    15     64600     T        99      99    14                                    16     64477     T        0.135   0.036 15                                    17     64527     T        0.116   0.055 15                                    18     64601     T        0.325   0.128 15                                    19     64608     T        0.285   0.085 14                                    21     64171     T        1.5645  0.0575                                                                               8                                    22     64210     T        0.729   0.087 15                                    23     65795     T        0.625   0.204 15                                    25     66457     T        0.312   0.085 15                                    26     66809     T        0.183   0.038 15                                    27     68849     T        0.142   0.087 15                                    28c    64027     T        0.278   0.119  9                                    29d    65650     T        0.172   0.715 14                                    30c    65622     T        0.694   0.225 15                                    31c    65803     T        99      0.533 14                                    32c    66492     T        99      2.86  14                                    33     67440     T        0.102   0.045 14                                    34d    65983     T        0.07    0.042 14                                    39c    66995     T        0.187   0.035 15                                    36d    67330     T        1.322   0.371 15                                    37     67372     T        0.352   0.91  15                                    38     64312     T        99      0.839 15                                    39     67366     T        99      1.848 15                                    41     66811     T        99      99    13                                    42     66810     T        99      99    13                                    43     67891     T        99      99     9                                    44     67753     T        0.198   0.385 14                                    44     67706     T        99      0.608 11                                    451    64046     T        0.558   0.153 13                                    46c    64066     T        0.197   0.1   15                                    47     63924     T        5.145   0.057 15                                    48     67487     T        0.464   0.213 15                                    49d    68656     T        99      99     9                                    49g    68193     B        99      49.859                                                                              10                                    50a    68746     B        49.5505 0.065  8                                    50b    68835     B        49.578  0.092  8                                    50d    68801     B        0.153   0.052  9                                    51g    68377     B        99      0.2625                                                                              10                                    51h    68625     B        0.792   0.135 10                                    52b    68012     T        0.247   0.0295                                                                              14                                    52c    68019     T        0.404   0.044 11                                    53     67983     T        0.194   0.072 15                                    54a    68915     B        49.5925 0.016  8                                    54e    64751     T        99      0.1045                                                                              14                                    56d    64188     T        1.465   0.634 14                                    56e    65805     T        99      5.304 11                                    57     68350     B        99      99     9                                    58a    64239     T        99      99    12                                    58d    65819     T        99      99    14                                    58e    66458     T        99      99    14                                    60e    68307     B        99      0.4145                                                                              10                                    60h    68357     B        0.328   0.0315                                                                              10                                    61e    67736     T        0.706   0.3355                                                                              14                                    62f    67340     T        0.213   0.09  15                                    63d    68743     B        0.304   0.13   7                                    ______________________________________                                    

Using the method described above, Example 1e was tested against otherviruses.

The Minimum Inhibitory Concentration (MIC) for the 15 most commonlyisolated nonpolio enteroviruses (Strikas, R. A., Anderson, L. J., andParker, R. A., 1986; Temporal and Geographic Patterns of Isolates ofNonpolio Enterovirus in the United States, 1970-1983. J. Infect.Diseases, 153:346-351) listed below: Echovirus 3, Echovirus 4, Echovirus5, Echovirus 6, Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 24,Echovirus 30, Coxsackievirus B1, Coxsackievirus B2, Coxsackievirus B3,Coxsackievirus B4, Coxsackievirus B5, Coxsackievirus A9, was determined(using the method described above) for Example 1 e, giving an overallMIC₈₀ of 0.05 μM. MIC₅₀ for coxsaciviruses A9, A21 and B3 were 0.005 μM,0.04 μM and 0.002 μM respectively.

In Vivo Studies

Efficacy data was generated in mouse models of enterovirus infections.Results in a severe disseminated enterovirus infection model in mice(coxsackievirus B3 infection) indicate that Example 1e has shownefficacy in this stringent model.

In a three-part study, Example 1e was administered orally to mice tostudy its ability to prevent death or paralysis caused by variousnon-polio enteroviruses. In each part of this study, the mice wereinfected with an amount of virus shown to result in 80% paralysis and/ordeath in untreated animals. The animals were then administered Example1e at various doses prepared in 0.5% xanthan gum with 1% Tween 80. Theresults of this study are summarized in Tables 3-5.

One part of this study determined the compound's efficacy againstcoxsackievirus A9 in 150 suckling ICR pups infected subcutaneouslywithin 24 hours of birth. The drug was administered daily for five daysbeginning 2.5 days postinfection. The results of this part of the studyare presented in Table 3. Based on the analysis of the resultssummarized in Table 3, the 50% protective dose (PD₅₀) was determined tobe 88 mg/kg per day against coxsackievirus A9.

In another study of the oral efficacy of Example 1e against acoxsackievirus A9 infection in suckling mice, in which the compound wasadministered once 2.5 days postinfection, the 50% protective dose wasdetermined to be 93 mg/kg per day.

                  TABLE III                                                       ______________________________________                                        Summary of Antienterovirus Activity of Example 1e                             Administered Orally to Mice:                                                  Coxsackievirus A9 [2]                                                         Dose           % Nonparalyzed                                                 (mg/kg per day)                                                                              at Day 13                                                      ______________________________________                                        0              17                                                             0.2             7                                                             2.0            10                                                             20             10                                                             200            87                                                             ______________________________________                                    

Another part of the study determined the efficacy of Example 1e againstcoxsackievirus A21 in 200 weanling ICR mice. The drug was administeredon Day 1 two hours prior to infection and two hours after infection. OnDay 2 through Day 5, the drug was administered twice a day. The resultsof this part of the study are presented in Table IV. Based on theanalysis of the results summarized in Table IV, the PD₅₀ was determinedto be 26 mg/kg per day against coxsackievirus A21 in weanling mice.

                  TABLE IV                                                        ______________________________________                                        Summary of Antienterovirus Activity of Example 1e                             Administered Orally to Mice:                                                  Coxsackievirus A21 [2]                                                        Dose            % Alive                                                       (mg/kg per day) at Day 17                                                     ______________________________________                                         0              15                                                             9.4            13                                                            18.8            40                                                            37.5            75                                                            75              100                                                           ______________________________________                                    

The third part of the study determined the efficacy of Example 1eagainst coxsackievirus B3 in adult male BALB/c mice. The drug wasadministered on Day 1 two hours prior to infection and two hours afterinfection. On Day 2 through Day 5, the drug was administered twice aday. The results of this part of the study are presented in Table V.Based on the analysis of the results summarized in Table V, the 50%protective dose (PD₅₀) was determined to be 12 mg/kg per day againstcoxsackievirus B3 in adult male mice.

                  TABLE V                                                         ______________________________________                                        Summary of Antienterovirus Activity of Example 1e                             Administered Orally to Mice:                                                  Coxsackievirus B3 [2]                                                         Dose            % Alive                                                       (mg/kg per day) at Day 17                                                     ______________________________________                                         0              13                                                             2               8                                                             20             67                                                            200             92                                                            ______________________________________                                    

Example 1e was orally effective in protecting mice infected withcoxsackievirus A9, A21 and B3. Results from a study to determine theefficacy of Example 1e against coxsackievirus A9 in suckling miceindicate that the 50% protective dose (PD₅₀) was approximately 88 mg/kgper day. The PD₅₀ of Example 1e against coxsackievirus A21 in weanlingmice was determined to be approximately 26 mg/kg per day, and the PD₅₀of Example 1e against coxsackievirus B3 in adult male mice wasdetermined to be approximately 12 mg/kg per day.

The compounds of formula I can be formulated into compositions,including sustained release compositions together with one or morenon-toxic physiologically acceptable carriers, adjuvants or vehicleswhich are collectively referred to herein as carriers, in anyconventional form, using conventional formulation techniques forpreparing compositions for treatment of infection or for propylacticuse, using formulations well known to the skilled pharmaceuticalchemist, for parenteral injection or oral or nasal administration, insolid or liquid form, for rectal or topical administration, or the like.

The compositions can be administered to humans and animals eitherorally, rectally, parenterally (intravenous, intramuscularly orsubcutaneously), intracisternally, intravaginally, intraperitoneally,locally (powders, ointments or drops), or as an aerosal, for example asa nasal or a buccal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, polyalkylene glycols and the like),suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionsand by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents that delay absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, lozenges and granules which may be dissolved slowly inthe mouth, in order to bathe the mouth and associated passages with asolution of the active ingredient. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (c) humectants, as for example, glylcerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as, for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate, (h) adsorbents, as, for example, kaolin and bentonite, and(i) lubricants, as, for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate or mixturesthereof. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents.

Certain solid dosage forms may be delivered through the inhaling of apowder manually or through a device such as a SPIN-HALER used to deliverdisodium cromoglycate, INTAL. When using the latter device, the powdercan be encapsulated. When employing a liquid composition, the drug canbe delivered through a nebulizer, an aerosol vehicle, or through anydevice which can divide the composition into discrete portions, forexample, a medicine dropper or an atomizer.

Solid compositions of a similar type may also formulated for use in softand hard gelatin capsules, using such excipients as lactose or milksugar as well as high molecular weight polyethyleneglycols, and thelike.

Solid dosage forms such as tablets, dragees, capsules, pills andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Alsosolid formulations may be prepared as a base for liquid formulations. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, particularly cottonseed oil, ground-nut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like. Besides suchinert diluents, the composition can also include adjuvants, such aswetting agents, emulsifying and suspending agents, sweetening, flavoringand perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethyleneglycol or a suppository wax, which aresolid at ordinary temperatures but liquid at body temperature and,therefore, melt in the rectum or vaginal cavity and release the activecomponent.

Compositions for administration as aerosols are prepared by dissolving acompound of Formula I in water or a suitable solvent, for example analcohol ether, or other inert solvent, and mixing with a volatilepropellant and placing in a pressurized container having a meteringvalve to release the material in usefule droplet size.

The liquefied propellant employed typically one which has a boilingpoint below ambient temperature at atmospheric pressure. For use incompositions intended to produce aerosols for medicinal use, theliquefied propellant should be non-toxic. Among the suitable liquefiedpropellants which may be employed are the lower alkanes containing up tofive carbon atoms, such as butane and pentane, or a lower alkylchloride, such as methyl, ethyl, or propyl chlorides. Further suitableliquefied propellants are the fluorinated and fluorochlorinated loweralkanes such as are sold under the trademarks "Freon" and "Genetron".Mixtures of the abovementioned propellants may suitably be employed.

The specifications for the novel unit dosage forms of this invention aredictated by and directly dependent on (a) the unique characteristics ofthe active material and the particular effect to be achieved and (b) thelimitations inherent in the art of compounding such an active materialfor use in humans and animals, as disclosed in detail in thisspecification, these being features of the present invention. Examplesof suitable unit dosage forms in accord with this invention are capsulesadapted for insufflation, dropperfuls, aerosols with metered discharges,segregated multiples of any of the foregoing, and other forms as hereindescribed.

Compounds of the invention are useful for the prophylaxis and treatmentof infections of suspected picornaviral etiologies such as asepticmeningitis, upper respiratory tract infection, enterovirus infections,coxsackievirus, enteroviruses and the like. An effective but non-toxicquantity of the compound is employed in treatment. The dosage of thecompound used in treatment depends on the route of administration, e.g.,intra nasal, intra bronchial, and the potency of the particularcompound.

Dosage forms for topical administration include ointments, powders,sprays and inhalants. The active component is admixed under sterileconditions with a physiologically acceptable carrier and anypreservatives, buffers or propellants as may be required. Opthalmicformulations, eye ointments, powders and solutions are alsocontemplated.

Actual dosage levels of the active ingredient in the compositions may bevaried so as to obtain an amount of active ingredient that is effectiveto obtain a desired therapeutic response for a particular compositionand method of administration. The selected dosage level thereforedepends upon the desired therapeutic effect, on the route ofadministration, on the desired duration of treatment and other factorsand is readily determined by those skilled in the art.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the body weight,general health, sex, diet, time and route of administration, rates ofabsorption and excretion, combination with other drugs and the severityof the disease being treated and is readily determined by the skilledclinician.

Because compounds within the scope of the above invention are able tosuppress the growth of viruses when added to a medium in which the virusis growing, it is specifically contemplated that compounds of theinvention can therefore be used in aqueous solution, for example with asurfactant, to decontaminate surfaces on which polio, Coxsackie,rhinovirus and other viruses are present, such surfaces including, butnot limited to, hospital glassware, hospital working surfaces andsimilar areas in the preparation of food.

Hand contact of nasal mucus may be the most important mode of rhinovirustransmission. Sterilization of the hands of people coming into contactwith persons infected with rhinovirus would be a method for preventingfurther spread of the disease. If a compound of the invention wereincorporated into a hand washing or hand care procedure they wouldinhibit production of rhinovirus and decrease the likelihood of thetransmission of the disease.

When administered prior to injection, that is, prophylactically, it ispreferred that the administration be within about 0 to 48 hours prior toinfection of the host animal with the pathogenic virus. Whenadministered therapeutically to inhibit an infection it is preferredthat the administration be within about a day or two after infectionwith the pathogenic virus.

The dosage unit administered will be dependent upon the virus for whichtreatment or prophylaxis is desired, the type of animal involved, itsage, health, weight, extent of infection, kind of concurrent treatment,if any, frequency of treatment and the nature of the effect desired.

What is claimed is:
 1. A compound of the formula ##STR25## wherein: R₁is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl,hydroxyalkoxy, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxyor cyanomethyl;Y is alkylene of 3 to 9 carbon atoms, R₂ and R₃independently are hydrogen, alkyl, alkoxy, halo, cyano, trifluoromethylor nitro; R₄ is alkoxy, hydroxy, halomethyl, dihalomethyl,trihalomethyl, dihaloethyl, cycloalkyl, heterocyclyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, halo,thioalkyl, alkylthioalkyl, alkylthio, thio, 2,2,2-trifluoroethyl,(4-methylphenyl)sulfonyloxymethyl, N=Q or CON=Q, where N=Q is amino,alkylamino or dialkylamino; R₅ is halo or hydrogen, or alkyl.
 2. Acompound according to claim 1 of the formula ##STR26## wherein: R₁ isalkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl,hydroxyalkoxy;Y is alkylene of 3 to 9 carbon atoms; R₂ and R₃ areindependently hydrogen, alkyl, alkoxy, halo, trifluoromethyl or nitro;R₄ is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl,cycloalkyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,alkanecarbonyloxyalkyl, cyano, (4-methylphenyl)sulfonyloxymethyl, N=Q orCON=Q, wherein N=Q is amino, alkylamino or dialkylamino.
 3. A compoundaccording to claim 2 wherein:R₁ is C₁₋₅ -alkyl, C₁₋₅ -alkoxy, hydroxy,cyclopropyl, hydroxy-C₁₋₅ -alkyl, C₁₋₅ -alkoxy-C₁₋₅ -alkyl orhydroxy-C₁₋₅ -alkoxy, methylthiomethyl, methylsulfonylmethyl,methylsulfinylmethyl; R₂ and R₃ independently are hydrogen, C₁₋₃ -alkylor halo; and R₄ is C₁₋₃ -alkoxy, hydroxy, halomethyl, dihalomethyl,trihalomethyl, cyclopropyl, C₁₋₃ -alkoxycarbonyl, hydroxy-C₁₋₃ -alkyl,C₁₋₃ -alkoxy-C₁₋₃ -alkyl, (C₁₋₃ -alkyl, (C₁₋₃ -alkane)carboxyloxy-C₁₋₃-alkyl, 1,1-difluoroethyl, cyano, 2,2,2-trifluoroethyl,4-(methylphenyl)sulfonyl-oxymethyl, N=Q or CON=Q, where N=Q is amino,C₁₋₃ -alkylamino or di-(C₁₋₃ -alkyl)amino.
 4. A compound according toclaim 3 wherein Y is alkylene of 3 to 5 carbon atoms.
 5. A compoundaccording to claim 2 of the formula ##STR27##
 6. A compound according toclaim 5 wherein:R₁ is C₁₋₅ -alkyl, C₁₋₅ -alkoxy, hydroxy, cyclopropyl,hydroxy-C₁₋₅ -alkyl, C₁₋₅ -alkoxy-C₁₋₅ -alkyl or hydroxy-C₁₋₅ -alkoxy,methylthiomethyl, methylsulfinylmethyl, methylsulfonylmethyl; R₂ and R₃independently are hydrogen, C₁₋₅ -alkyl or halo; and R₄ is C₁₋₃ -alkoxy,hydroxy, halomethyl, dihalomethyl, trihalomethyl, cyclopropyl, C₁₋₃-alkoxycarbonyl, hydroxy-C₁₋₃ -alkyl, C₁₋₃ -alkoxy-C₁₋₃ -alkyl, (C₁₋₃-alkane)carbonyloxy-C₁₋₃ -alkyl, cyano, 1,1-difluoroethyl,2,2,2-trifluoroethyl, 4-(methylphenyl)sulfonyl-oxymethyl, N=Q or CON=Q,where N=Q is amino, C₁₋₃ -alkylamino or di-(C₁₋₃ -alkyl)amino.
 7. Acompound according to claim 6 wherein Y is alkylene of 3 to 5 carbonatoms.
 8. A compound according to claim 7 wherein R₄ is C₁₋₃ -alkoxy,fluoromethyl, dihalomethyl, trihalomethyl, cyclopropyl or C₁₋₃-alkoxy-C₁₋₃ -alkyl.
 9. A compound according to claim 8 wherein Y isalkylene of 3 to 5 carbon atoms.
 10. A compound according to claim 9selected from the group consistingof:5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-methylisoxazole;5-{3-[2,6-dimethyl-4-(5-methoxymethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole;5-{3-[2,6-dimethyl-4-(5-fluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole;5-{3-[2,6-dimethyl-4-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole;5-{3-[4-(5-dichloromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-methylisoxazole;5-{3-[4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-methylisoxazole;5-{3-[2,6-dimethyl-4-(5-methoxy-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole;5-{3-[2,6-dimethyl-4-(5-ethoxy-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-3-methylisoxazole;5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-ethylisoxazole;5-{3-[5-(cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-(methoxymethyl)isoxazole;5-{3-[5-(cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-cyclopropyl-isoxazole;5-(3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-(hydroxymethyl)isoxazole;5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-hydroxyisoxazole;5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-ethoxyisoxazole;and5-{3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl}-3-(2-hydroxyethoxy)isoxazole.11. A composition for combatting picornaviruses which comprises anantivirally effective amount of a compound according to claim 2 inadmixture with a suitable pharmaceutical carrier or diluent.
 12. Acomposition according to claim 11 for combatting rhinoviruses.
 13. Acomposition for combatting picornaviruses which comprises an antivirallyeffective amount of a compound according to claim 5 in admixture with asuitable pharmaceutical carrier or diluent.
 14. A composition accordingto claim 13 for combatting rhinoviruses.
 15. A method for combattingpicornaviruses which comprises contacting the locus of said viruses witha compound according to claim
 1. 16. A method for combattingpicornaviruses which comprises contacting the locus of said viruses witha compound according to claim
 2. 17. A method for combattingpicornaviruses which comprises contacting the locus of said viruses witha compound according to claim
 5. 18. A method for combatting apicornaviral infection in a mammalian host which comprises administeringto said host an antivirally effective amount of a composition accordingto claim
 13. 19. A method for combatting a rhinovirus infection in amammalian host which comprises administering to said host an antivirallyeffective amount of a composition according to claim
 12. 20. A methodfor combatting a rhinovirus infection in a mammalian host whichcomprises administering to said host an antivirally effective amount ofa composition according to claim
 14. 21. A compound of the formula##STR28## wherein: Y is alkylene of 3 to 9 carbon atoms;R₂ and R₃independently are hydrogen, alkyl, alkoxy, halo, trifluoromethyl ornitro; and R₆ is alkoxy, fluoromethyl, difluoromethyl, trihalomethyl,cycloalkyl or alkoxyalkyl.
 22. A compound according to claim 21 selectedfrom3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-5-tri-fluoromethyl-1,2,4-oxadiazoleand5-cyclopropyl-3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-1,2,4-oxadiazole23. A compound of the formula ##STR29## wherein: R₂ and R₃ independentlyare hydrogen, alkyl, alkoxy, halo, trifluoromethyl or nitro; andR₇ isalkoxy, fluoromethyl, difluoromethyl, tri-fluoromethyl, cycloalkyl,alkoxyalkyl or cyano.
 24. A compound according to claim 23 selected from3-(3,5-dimethyl-4-hydroxyphenyl)-5-trifluoromethyl-1,2,4-oxadiazole,3-(3,5-dichloro-4-hydroxyphenyl)-5-tri-fluoromethyl-1,2,4-oxadiazole and3-(4-hydroxyphenyl)-5-tri-fluoromethyl-1,2,4-oxadiazole.
 25. A compoundof the formula ##STR30## wherein: Y is alkylene of 3 to 9 carbonatoms;R₂ and R₃ independently are hydrogen, alkyl, alkoxy, halo,trifluoromethyl or nitro; R₄ is cycloalkyl or alkoxyalkyl; and R₈ isalkyl. 26.5-Cyclopropyl-3-[4-(5-ethoxycarbonyl-4-pentynyloxy)-3,5-dimethylphenyl]-1,2,4-oxadiazoleaccording to claim
 25. 27. A compound according to claim 1 wherein R₅ ishydrogen and R₂ and R₃ are in 2,6 positions and Y is propylene.
 28. Acompound according to claim 27 wherein R₁ is alkylthioalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, dialkylaminoalkyl,alkylaminoalkyl, aminoalkyl, carboxy, or cyanomethyl.
 29. A compoundaccording to claim 28 wherein R₁ is chosen from the group consisting of;methyl, ethylthiomethyl, ethylsulfinylmethyl, ethylsulfonylmethyl,methylthiomethyl, methylsulfinylmethyl, methylsulfonylmethyl,dimethylaminomethyl, cyanomethyl and carboxy.
 30. A composition forcombatting picornaviruses which comprises an antivirally effectiveamount of a compound according to claim 27 in admixture with a suitablepharmaceutical carrier or diluent.
 31. A composition for combattingpicornaviruses which comprises an antivirally effective amount of acompound according to claim 28 in admixture with a suitablepharmaceutical carrier or diluent.
 32. A composition for combattingpicornaviruses which comprises an antivirally effective amount of acompound according to claim 29 in admixture with a suitablepharmaceutical carrier or diluent.
 33. A method for combatting apicornaviral infection in a mammalian host which comprises administeringto said host an antivirally effective amount of a composition accordingto claim
 30. 34. A method for combatting a picornaviral infection in amammalian host which comprises administering to said host an antivirallyeffective amount of a composition according to claim
 31. 35. A methodfor combatting a picornaviral infection in a mammalian host whichcomprises administering to said host an antivirally effective amount ofa composition according to claim 32.